Cyclic amide derivative

ABSTRACT

[Problem] 
     To provide a GPR40 activating agent having, as an active ingredient, a novel compound having a GPR40 agonist action, a salt of the compound, a solvate of the salt or the compound, or the like, particularly, an insulin secretagogues and a prophylactic and/or therapeutic agent against diabetes, obesity, or other diseases. 
     [Means of Solving the Problem] 
     A compound of Formula (1): 
     
       
         
         
             
             
         
       
         
         
           
             (where n is 0 to 2; p is 0 to 4; h is 0 to 3; j is 0 to 3; k is 0 to 2; a ring B is an aryl group or a heteroaryl group; X is O, S, or —NR 7 —; J 1  is —CR 11a R 11b — or —NR 11c —; J 2  is —CR 12a R 12b — or —NR 12c —; and R 1  to R 12c  are specific groups), 
             a salt of the compound, or a solvate of the salt or the compound.

TECHNICAL FIELD

The present invention relates to a compound for modulationg thefunctions of G protein-coupled receptor 40 (GPR40). In particular, thepresent invention relates to a compound having a saturated cyclic amidestructure having —S(O)_(n)—NH—CO— (n is an integer of 0 to 2) bonded toa ring B (hereinafter, referred to as the cyclic amide structure) ofFormula (I), a salt of the compound, a solvate of the compound or thesalt, a pharmaceutical composition containing the compound as an activeingredient, prophylactic and/or therapeutic agents againstGPR40-involving diseases, especially diabetes, and an insulinsecretagogues.

BACKGROUND ART

Diabetes is categorized into Type 1 diabetes (insulin-dependentdiabetes) and Type 2 diabetes (non-insulin-dependent diabetes), andboederline type diabetes (glucose tolerance disorders) has alsoattracted attention as a pre-diabetic condition in recent years. Type 1diabetes is characterized by a partial or complete inability to produceinsulin, which is a blood glucose regulating hormone. Type 2 diabetes ischaracterized by induced peripheral insulin resistance and impairedinsulin secretion. Borderline type diabetes is a pathological conditionexhibiting impaired glucose tolerance (IGT) or impaired fasting glucose(IFG), associated with a risk of developing Type 2 diabetes or diabetescomplications.

Diabetes is caused by several predisposing factors. It is a diseasecharacterized by high glucose levels in blood plasma in fasting andpostprandial states or during an oral glucose tolerance test or bychronic hyperglycemia, in general. Controlling chronic hyperglycemia isessential in clinical management and treatment of diabetes. Inparticular, reduced insulin secretion from beta cells of the pancreascan induce an abrupt increase in postprandial blood glucose levels inType 2 diabetes or boederline type diabetes. An internationallarge-scale clinical trial has revealed that it is essential to controlpostprandial hyperglycemia in impaired glucose tolerance for suppressingthe development and progress of not only diabetes but also hypertensionand cardiovascular diseases (JAMA, 290, 486-494 (2003) (Non-PatentDocument 1)). On the basis of these findings, the International DiabetesFederation published new guidelines for diabetes treatment (postprandialblood glucose control guidelines) in 2007, which recommend control ofpostprandial blood glucose levels as essential for Type 1 and 2 diabeticpatients to alleviate diabetes and reduce risk of complications. As apractical step, an increased administration of an alpha-glucosidaseinhibitor (voglibose) that is a drug for alleviating excessivepostprandial blood glucose levels associated with diabetes, has beenapproved in Japan as a prophylactic agent against diabetes, aiming to“inhibit the development of Type 2 diabetes from impaired glucosetolerance”. As described above, there has been increasing awareness ofthe needs of nonpharmacological and pharmacological treatments againstdiabetes and boederline type diabetes, targeting the control ofpostprandial blood glucose levels in recent years.

Diabetes is treated mainly through diet regulation and exercise. Whenthese fail to alleviate symptoms, pharmacological treatment is needed.Various types of drugs are available as prophylactic or therapeuticagents against diabetes. Among them, examples of insulin secretagoguesinclude sulfonylurea agents (e.g., glibenclamide, glimepiride) andrapid-acting insulin secretagogues (e.g., mitiglinide), all of whichstimulate beta cells of the pancreas so as to accelerate insulinsecretion. These drugs are, however, known for their ineffectiveness(primary failure, secondary failure) and side effects such as inducedhypoglycemic effects. Analogs (e.g., exenatide, liraglutide) ofglucagon-like peptide-1 (GLP-1), which are hormones acceleratingglucose-responsive insulin secretion in beta cells of the pancreas, havebecome available as novel insulin secretagogues, but they areadministered by injection and known for their side effects of transientgastrointestinal tract disorders. Other examples of insulinsecretagogues include dipeptidyl peptidase IV (DPP-IV) inhibitors (e.g.,sitagliptin, vildagliptin), which inhibit the degradation of intrinsicGLP-1, but they are known for their side effects of epipharyngitis,headache, and infections. Alpha-glucosidase inhibitors (e.g., acarbose,voglibose) inhibit the degradation and digestion of carbohydrate andthus limit an abrupt increase in postprandial blood glucose levels, butthey need to be taken immediately before meals and are known for theirside effects such as distension and diarrhea and serious liverdisorders. Biguanides (e.g., metformin, buformin) are insulin resistanceimproving agents enhancing insulin sensitivity and thereby alleviatinghyperglycemia, but are known to potentially induce side effects such aslactic acidosis, nausea, and vomiting. Thiazolidinedione derivatives(e.g., pioglitazone, rosiglitazone) are peroxisomeproliferator-activated receptor (PPAR) gamma agonists. The derivativesincrease insulin sensitivity in adipose tissue, the liver, and skeletalmuscles and thereby alleviate chronic hyperglycemia, but are known tocause edema, weight gain, and serious side effects of liver disorders.Side effects of these drugs do not always occur, but remain as a majorobstacle to high satisfaction with treatment. Therefore, the demand hasbeen increasing for insulin secretagogues, particularly orallyadministrable insulin secretagogues, entailing few problems and sideeffects caused by conventional prophylactic and therapeutic agents asdescribed above and inhibiting postprandial hyperglycemia withoutinducing hypoglycemia.

Fatty acid plays an important role in insulin use in the liver andskeletal muscles, glucose-responsive insulin secretion from thepancreas, and inflammation associated with fat accumulation in adiposetissue. A strong correlation is known between increased levels of fattyacid in blood plasma and the development of diabetes, metabolicsyndrome, obesity, and adiposity.

GPR40, one of the G-protein-coupled receptors, is categorized in thefree fatty acid receptor (FFAR) family and activated by C₆₋₂₂ saturatedor unsaturated fatty acid. It is reported that high expression of GPR40is observed in beta cells of the pancreas where the receptor is involvedin insulin secretion caused by fatty acid (Nature, 422, 173-176 (2003)(Non-Patent Document 2)). Non-fatty-acid low-molecular-weight compoundshaving a GPR40 agonist action have been found in recent years, and it isreported that thiazolidinediones, which are insulin sensitivityimproving agents, and MEDICA 16, which is a hypolipidemic agent, alsoexhibit agonist actions (Biochem. Biophys. Res. Comm., 301, 406-410(2003) (Non-Patent Document 3)).

In the pancreatic islets of Langerhans isolated from GPR40 knockoutmice, the glucose-responsive insulin secretagogue action of fatty acidis lower than the case with normal mice. Accordingly, substances havinga GPR40 agonist action like fatty acid are expected to have the effectof inhibiting postprandial hyperglycemia based on the glucose-responsiveinsulin secretagogue action in the pancreas. Therefore, substanceshaving a GPR40 agonist action are considered to be effective asprophylactic and therapeutic agents against diabetes or boederline typediabetes.

Studies have been progressed on compounds having a GPR40 activatingaction as insulin secretagogues or therapeutic agents against diabetes.Technologies related to compounds having a GPR40 agonist action aredisclosed, for example, in WO 2004/041266 pamphlet (Patent Document 1),WO 2005/086661 pamphlet (Patent Document 2), WO 2007/123225 pamphlet(Patent Document 3), WO 2008/001931 pamphlet (Patent Document 4), WO2009/054390 pamphlet (Patent Document 5), WO 2009/054423 pamphlet(Patent Document 6), WO 2009/054479 pamphlet (Patent Document 7), WO2011/046851 pamphlet (Patent Document 8), WO 2010/143733 pamphlet(Patent Document 9), WO 2007/033002 pamphlet (Patent Document 10), WO2009/048527 pamphlet (Patent Document 11), WO 2009/111056 pamphlet(Patent Document 12), WO 2005/051890 pamphlet (Patent Document 13), WO2004/022551 pamphlet (Patent Document 14), WO 2004/011446 pamphlet(Patent Document 15), WO 2008/030520 pamphlet (Patent Document 16), WO2011/066183 pamphlet (Patent Document 17), WO 2010/091176 pamphlet(Patent Document 18), WO 2010/085525 pamphlet (Patent Document 19), WO2009/039943 pamphlet (Patent Document 20), WO 2005/063729 pamphlet(Patent Document 21), and WO 2008/130514 pamphlet (Patent Document 22).These documents, however, do not disclose or suggest any compoundshaving a saturated cyclic amide structure bonded to a benzene ring orthe like.

A technique related to a compound having a 5-aryl-3-isothiazolidinonering is disclosed in WO 2005/035551 pamphlet (Patent Document 23). Thecompound disclosed in Patent Document 23, however, is a compound havingan inhibitory effect on protein tyrosine phosphatase 1B (PTP1B), and itsstructure of a linker moiety is fundamentally different from that of thecompounds according to the present invention.

Another compound group having a 5-aryl-3-isothiazolidinone ring isdisclosed in WO 2008/033931 pamphlet (Patent Document 24) as a compoundhaving an inhibitory effect on PTP1B. The compound disclosed in PatentDocument 24, however, has a fundamental framework different from that ofthe compounds according to the present invention.

Techniques related to compounds having a5-aryl-1,2,5-thiadiazolidin-3-one ring are disclosed in WO 2003/082841pamphlet (Patent Document 25), WO 2005/035551 pamphlet (Patent Document24), WO 2007/067612 pamphlet (Patent Document 26), WO 2007/067613pamphlet (Patent Document 27), WO 2007/067614 pamphlet (Patent Document28), WO 2007/089857 pamphlet (Patent Document 29), WO 2007/115058pamphlet (Patent Document 30), and WO 2009/109999 pamphlet (PatentDocument 31). The compounds disclosed in Patent Documents 24 to 31,however, are compounds having an inhibitory effect on PTP1B, and theirfundamental structures of linker moieties are different from that of thecompounds according to the present invention.

The compound having a 5-aryl-1,2,5-thiadiazolidin-3-one ring is alsodisclosed in WO 2008/022771 pamphlet (Patent Document 32). The compounddisclosed in Patent Document 32, however, is a compound having aninhibitory effect on sphingomyelin and having an amide structure on itslinker moiety, and is different from that of the compounds according tothe present invention.

A technique related to the compound having a5-aryl-1,2,6-thiadiazinan-3-one ring and a 5-aryl-1,2-thiazinan-3-onering is disclosed in Synlett, 834-838 (2005) (Non-Patent Document 4).The compound disclosed in Non-Patent Document 4, however, has afundamental framework different from that of the compounds according tothe present invention and does not disclose or suggest any compoundshaving a GPR40 agonist action like the present invention.

WO 2008/066131 pamphlet (Patent Document 33) and WO 2009/147990 pamphlet(Patent Document 34) disclose compounds having a3-hydroxy-5-arylisoxazolyl group as compounds having a G protein-coupledreceptor 120 (GPR120) agonist action. These documents, however, do notdisclose or suggest any compounds having a GPR40 agonist action or asaturated cyclic amide structure bonded to a benzene ring or the like asin the present invention.

WO 2011/052756 pamphlet (Patent Document 35) and WO 2011/078371 pamphlet(Patent Document 36) have recently disclosed compounds having a3-hydroxy-5-arylisoxazole group or a 3-hydroxy-5-arylisothiazole groupas compounds having a GPR40 activating action.

In the development of drugs, various strict criteria must be met interms of absorption, distribution, metabolism, excretion, and otherfactors as well as targeted pharmacological actions. There are variousthings to consider, for example, interaction with other drugs,desensitization or durability, digestive tract absorption after oraladministration, speed to reach the small intestine, absorption speed andfirst pass effect, organ barriers, protein binding, drug metabolizingenzyme induction or inhibition, excretion route and clearance in thebody, and application methods (application sites, methods, purposes). Itis difficult to find a drug that meets all the criteria.

Several compounds are reported to have a GPR40 agonist action, but noneof them has been marketed so far. Such agonists could also involve theabove-mentioned general issues in the development phase of drugs. Morespecifically, they have problems in usefulness and safety, such as lowmetabolism stability and difficulty in systemic exposure by oraladministration, unfavorable pharmacokinetic effects including absorptionand persistence properties, an activity of inhibiting the humanether-a-go-go related gene (hERG) channel, possibly resulting inarrhythmia, and an activity of inducing or inhibiting drug metabolizingenzymes (e.g., cytochrome P450). Therefore, required is a compound thatsolves these problems as much as possible and still has high efficacy.

In addition, required as a GPR40 agonist is a compound with fewerproblems or side effects as described above than the aforementionedconventional drugs that have been used to prevent or treat diabetes(particularly Type 2 diabetes or boederline type diabetes).

RELATED-ART DOCUMENTS Patent Documents

Patent Document 1: WO 2004/041266 pamphlet

Patent Document 2: WO 2005/086661 pamphlet

Patent Document 3: WO 2007/123225 pamphlet

Patent Document 4: WO 2008/001931 pamphlet

Patent Document 5: WO 2009/054390 pamphlet

Patent Document 6: WO 2009/054423 pamphlet

Patent Document 7: WO 2009/054479 pamphlet

Patent Document 8: WO 2011/046851 pamphlet

Patent Document 9: WO 2010/143733 pamphlet

Patent Document 10: WO 2007/033002 pamphlet

Patent Document 11: WO 2009/048527 pamphlet

Patent Document 12: WO 2009/111056 pamphlet

Patent Document 13: WO 2005/051890 pamphlet

Patent Document 14: WO 2004/022551 pamphlet

Patent Document 15: WO 2004/011446 pamphlet

Patent Document 16: WO 2008/030520 pamphlet

Patent Document 17: WO 2011/066183 pamphlet

Patent Document 18: WO 2010/091176 pamphlet

Patent Document 19: WO 2010/085525 pamphlet

Patent Document 20: WO 2009/039943 pamphlet

Patent Document 21: WO 2005/063729 pamphlet

Patent Document 22: WO 2008/130514 pamphlet

Patent Document 23: WO 2005/035551 pamphlet

Patent Document 24: WO 2008/033931 pamphlet

Patent Document 25: WO 2003/082841 pamphlet

Patent Document 26: WO 2007/067612 pamphlet

Patent Document 27: WO 2007/067613 pamphlet

Patent Document 28: WO 2007/067614 pamphlet

Patent Document 29: WO 2007/089857 pamphlet

Patent Document 30: WO 2007/115058 pamphlet

Patent Document 31: WO 2009/109999 pamphlet

Patent Document 32: WO 2008/022771 pamphlet

Patent Document 33: WO 2008/066131 pamphlet

Patent Document 34: WO 2009/147990 pamphlet

Patent Document 35: WO 2011/052756 pamphlet

Patent Document 36: WO 2011/078371 pamphlet

Non-Patent Documents

Non-Patent Document 1: JAMA, 290, 486-494 (2003)

Non-Patent Document 2: Nature, 422, 173-176 (2003)

Non-Patent Document 3: Biochem. Biophys. Res. Comm., 301, 406-410 (2003)

Non-Patent Document 4: Synlett, 834-838 (2005)

SUMMARY OF THE INVENTION Problem to be Solved by the Invention

In view of such medical circumstances related to diabetes, prophylacticand therapeutic drugs are required that accelerate insulin secretion,particularly glucose-responsive insulin secretion, through activation ofGPR40, and thus exhibit the action of lowering blood glucose levels,particularly inhibiting postprandial hyperglycemia.

Particularly required are orally administrable GPR40 activating agents,insulin secretagogues, prophylactic and/or therapeutic agents againstGPR40-involving diseases (particularly prophylactic and/or therapeuticagents against diabetes or obesity) all of which have high safety,excellent efficacy, and high selectivity with respect to other membersof the FFAR family or similar receptors.

In particular, there are issues to be addressed as problems with theconventional techniques described above. More specifically, there arethe following issues to be addressed with prophylactic and therapeuticagents against diabetes: ineffectiveness (primary failure, secondaryfailure) and side effects such as induced hypoglycemic effects caused bysulfonylurea agents and rapid-acting insulin secretagogues; transientgastrointestinal tract disorders caused by GLP-1 analogs; side effectsof epipharyngitis, headache, and infections caused by DPP-IV inhibitors;side effects such as distension and diarrhea and serious liver disorderscaused by alpha-glucosidase inhibitors; side effects such as lacticacidosis, nausea, and vomiting caused by biguanides; edema, weight gain,and serious liver disorders caused by thiazolidinedione derivatives; andso on. Other issues to be addressed include solubility, improvement inmetabolism stability, enhancement of absorption properties, improvementin pharmacokinetic effects, reduction in the activity of inhibitinghERG, and reduction in the activity of inducing or inhibiting drugmetabolizing enzymes (e.g., cytochrome P450). Consequently, there areneeds for insulin secretagogues and prophylactic and/or therapeuticagents against GPR40-involving diseases (particularly prophylacticand/or therapeutic agents against diabetes or obesity) all of whichsolve at least one of the issues, to be orally administrable to mammalsincluding human beings, and clinically usable in particular.

Means for Solving the Problem

As a result of assiduous research for solving the above problems byobtaining a compound having high safety and/or excellent efficacy andmodulationg the functions of GPR40, the inventors of the presentinvention have found that a derivative having a cyclic amide structureof Formula (I) has a GPR40 agonist action. The compound of the presentinvention has an excellent glucose-responsive insulin secretagogueaction and has a strong hyperglycemia-inhibiting action during glucoseload.

Effects of Invention

The present invention provides: a compound characterized by having acyclic amide structure of Formula (I), a salt of the compound, or asolvate of the compound or the salt; and a pharmaceutical compositioncharacterized by containing as an active ingredient, the compound, apharmaceutically acceptable salt of the compound, or a solvate of thecompound or the pharmaceutically acceptable salt.

The compound of the present invention is a compound having a GPR40agonist action, or a compound having an action of lowering a bloodglucose level, particularly an action of inhibiting postprandialhyperglycemia, by activating GPR40 to accelerate an insulin secretion,particularly a glucose-responsive insulin secretion. The pharmaceuticalcomposition containing the compound of the present invention as anactive ingredient can be orally administrated and is expected as aninsulin secretagogue or a prophylactic agent and/or a therapeutic agentfor a GPR40-involving disease, particularly diabetes (particularly Type2 diabetes or boederline type diabetes) or obesity and adiposity.

The group of the compounds of the present invention has at least one ofcharacteristics such as having advantageous solubility, having highmetabolism stability, having excellent oral absorption properties, andhaving a small activity of inhibiting the hERG channel, and thus ishighly useful.

MODES FOR CARRYING OUT THE INVENTION

The present invention provides: a compound of Formula (I), characterizedby having the cyclic amide structure shown in the following aspects, asalt of the compound, or a solvate of the compound or the salt; and apharmaceutical composition or GPR40 activating agent, characterized bycontaining the compound, the salt, or the solvate as an activeingredient.

[Aspects of the Present Invention]

-   [1] Aspect [1] of the present invention

A first aspect of the present invention is a compound of Formula (I):

(where n is an integer of 0 to 2; p is an integer of 0 to 4; h is aninteger of 0 to 3; j is an integer of 0 to 3; k is an integer of 0 to 2;

-   a ring A is a C₆₋₁₄ aryl group which is optionally substituted with    1 to 5 L(s), a 3- to 14-membered heterocyclic group which is    optionally substituted with 1 to 5 L(s), a C₅₋₇ cycloalkyl group    which is optionally substituted with 1 to 5 L(s), a C₅₋₇    cycloalkenyl group which is optionally substituted with 1 to 5 L(s),    a 6- to 14-membered spiro ring group which is optionally substituted    with 1 to 5 L(s), or a 2-phenylamino-2-oxoacetyl group which is    optionally substituted with 1 to 5 L(s);-   a ring B is a C₆₋₁₄ aryl group or a 5- to 14-membered heteroaryl    group;-   X is an oxygen atom, a sulfur atom, or —NR⁷—;-   J₁ is —CR^(11a)R^(11b)— or —NR^(11c)—; J₂ is —CR^(12a)R^(12b)— or    —NR^(12c)— (with the proviso that when J₁ is —NR^(11c)—, h is 0);-   R¹s are independently a group optionally selected from a halogen    atom, a C₁₋₆ alkyl group which is optionally substituted with 1 to 5    substituent(s) RI, a C₂₋₆ alkenyl group which is optionally    substituted with 1 to 5 substituent(s) RI, a C₂₋₆ alkynyl group    which is optionally substituted with 1 to 5 substituent(s) RI, a    C₁₋₆ alkoxy group which is optionally substituted with 1 to 5    substituent(s) RI, and a cyano group;-   R^(2a) and R^(2b) are independently a group optionally selected from    a hydrogen atom, a halogen atom, a C₁₋₆ alkyl group, a C₂₋₆ alkenyl    group, a C₂₋₆ alkynyl group, a C₁₋₆ alkoxy group, and a cyano group;-   R³, R⁴, R⁵, R⁶, and R⁷ are independently a group optionally selected    from a hydrogen atom, a C₁₋₆ alkyl group, a halogenated C₁₋₆ alkyl    group, a C₂₋₆ alkenyl group, and a C₂₋₆ alkynyl group;-   R^(11a) and R^(11b) are independently a group optionally selected    from a hydrogen atom, a halogen atom, a C₁₋₆ alkyl group, a    halogenated C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, a C₂₋₆ alkynyl    group, a C₁₋₆ alkoxy group, a halogenated C₁₋₆ alkoxy group, a C₂₋₇    alkanoyl group, and a carboxy group which is optionally protected;-   R^(12a) and R^(12b) are independently a group optionally selected    from a hydrogen atom, a halogen atom, a C₁₋₆ alkyl group, a    halogenated C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, a C₂₋₆ alkynyl    group, a C₁₋₆ alkoxy group, a halogenated C₁₋₆ alkoxy group, and a    cyano group;-   R^(11c) and R^(12c) are independently a group optionally selected    from a hydrogen atom, a C₁₋₆ alkyl group, and a halogenated C₁₋₆    alkyl group;    with the proviso that in the cyclic amide structure moiety, there is    not one of the substituents (R^(2b), R^(11b), R^(11c), R^(12b), or    R^(12c)) on an atom to which the ring B is bonded;-   Ls are independently a group optionally selected from a halogen    atom, —OH, an oxo group, a cyano group, a C₁₋₁₀ alkyl group which is    optionally substituted with 1 to 5 substituent(s) RI, a C₂₋₁₀    alkenyl group which is optionally substituted with 1 to 5    substituent(s) RI, a C₂₋₁₀ alkynyl group which is optionally    substituted with 1 to 5 substituent(s) RI, a C₁₋₁₀ alkoxy group    which is optionally substituted with 1 to 5 substituent(s) RI, a    C₂₋₁₀ alkenyloxy group which is optionally substituted with 1 to 5    substituent(s) RI, a C₂₋₁₀ alkynyloxy group which is optionally    substituted with 1 to 5 substituent(s) RI, an aryl group which is    optionally substituted with 1 to 5 substituent(s) RII, a    heterocyclic group which is optionally substituted with 1 to 5    substituent(s) RII, an aralkyl group which is optionally substituted    with 1 to 5 substituent(s) RII, a heteroarylalkyl group which is    optionally substituted with 1 to 5 substituent(s) RII, a    non-aromatic heterocyclic alkyl group which is optionally    substituted with 1 to 5 substituent(s) RII, an aryloxy group which    is optionally substituted with 1 to 5 substituent(s) RII, a    heteroaryloxy group which is optionally substituted with 1 to 5    substituent(s) RII, a non-aromatic heterocyclic oxy group which is    optionally substituted with 1 to 5 substituent(s) RII, an aralkyloxy    group which is optionally substituted with 1 to 5 substituent(s)    RII, a heteroarylalkyloxy group which is optionally substituted with    1 to 5 substituent(s) RII, —SH, —SF₅, a —S(O)_(i)R^(a) (i is an    integer of 0 to 2) group, a —NR^(b)R^(c) group, and a substituted    spiropiperidinylmethyl group;

R^(a) is a C₁₋₆ alkyl group or a halogenated C₁₋₆ alkyl group;

-   R^(b) and R^(c) are independently a group optionally selected from a    hydrogen atom, a C₁₋₆ alkyl group, a halogenated C₁₋₆ alkyl group, a    C₂₋₆ alkenyl group, a C₂₋₆ alkynyl group, a C₂₋₇ alkanoyl group (the    alkanoyl group is optionally substituted with —OH or a C₁₋₆ alkoxy    group), a C₁₋₆ alkylsulfonyl group, an arylcarbonyl group, and a    heterocyclic carbonyl group, where R^(b) and R^(c) optionally form    together with a nitrogen atom to which they are bonded, a 3- to    8-membered cyclic group, where in the cyclic group, one or two    carbon atom(s) is(are) optionally substituted with an atom    optionally selected from an oxygen atom, a sulfur atom, and a    nitrogen atom (the nitrogen atom is optionally substituted with a    C₁₋₆ alkyl group which is optionally substituted with 1 to 5    substituent(s) RI) or with a carbonyl group, and the cyclic group is    optionally further substituted with 1 to 5 substituent(s) RII;-   where the substituents RI may be the same as or different from each    other and be each a group optionally selected from a halogen atom,    —OH, a cyano group, a C₁₋₆ alkoxy group (the C₁₋₆ alkoxy group is    optionally substituted with 1 to 5 halogen atom(s), 1 to 5 —OH, 1 to    5 C₁₋₆ alkoxy group(s), 1 to 5 aryl group(s) (the aryl group is    optionally substituted with 1 to 3 halogen atom(s)), 1 to 5    heterocyclic group(s) (the heterocyclic group is optionally    substituted with 1 to 3 C₁₋₆ alkyl group(s) or 1 to 3 oxo group(s)),    1 to 5—S(O)_(i)R^(a) (i is an integer of 0 to 2) group(s), 1 to 5    —SO₂NR^(d)R^(e) group(s), 1 to 5 —CONR^(d)R^(e) group(s), or 1 to 5    —NR^(b1)R^(c1) group(s)), a —NR^(b1)R^(c1) group, and a heterocyclic    oxy group (the heterocyclic oxy group is optionally substituted with    1 to 3 C₁₋₆ alkyl group(s) or 1 to 3 oxo group(s));-   the substituents RII may be the same as or different from each other    and be each a group optionally selected from the substituents RI, a    C₁₋₆ alkyl group (the C₁₋₆ alkyl group is optionally substituted    with 1 to 5 halogen atom(s), 1 to 5 —OH, 1 to 5 C₁₋₆ alkoxy    group(s), 1 to 5 —S(O)_(i)R^(a) (i is an integer of 0 to 2)    group(s), 1 to 5 —NR^(b1)R^(c1) group(s), 1 to 5 —SO₂NR^(d)R^(e)    group(s), or 1 to 5 —CONR^(d)R^(e) group(s)), a C₂₋₆ alkenyl group,    a C₂₋₇ alkanoyl group, an aralkyloxy group, a heterocyclic group    (the heterocyclic group is optionally substituted with 1 to 3 C₁₋₆    alkyl group(s) or 1 to 3 oxo group(s)), a heterocyclic carbonyl    group (the heterocyclic carbonyl group is optionally substituted    with 1 to 3 C₁₋₆ alkyl group(s) or 1 to 3 oxo group(s)), a    —S(O)_(i)R^(a) (i is an integer of 0 to 2) group, a —CONR^(d)R^(e)    group, and a —CONR^(d)R^(e1) group;-   R^(d) and R^(e) are independently a hydrogen atom or a C₁₋₆ alkyl    group (the C₁₋₆ alkyl group is optionally substituted with 1 to 5    halogen atom(s), 1 to 5 —OH, or 1 to 5 C₁₋₆ alkoxy group(s));-   R^(e1) is a C₁₋₆ alkyl group (the C₁₋₆ alkyl group is substituted    with 1 to 5 —OH, 1 to 5 C₁₋₆ alkoxy group(s), 1 to 5 aryl group(s)    (the aryl group is optionally substituted with 1 to 3 halogen    atom(s)), 1 to 5 heterocyclic group(s) (the heterocyclic group is    optionally substituted with 1 to 3 C₁₋₆ alkyl group(s) or 1 to 3 oxo    group(s)), 1 to 5—S(O)_(i)R^(a) (i is an integer of 0 to 2)    group(s), 1 to 5 —SO₂NR^(d)R^(e) group(s), 1 to 5 —CONR^(d)R^(e)    group(s), or 1 to 5 —NR^(b1)R^(c1) group(s));-   R^(b1) and R^(c1) are independently a group optionally selected from    a hydrogen atom, a C₁₋₆ alkyl group, a C₂₋₇ alkanoyl group, and a    C₁₋₆ alkylsulfonyl group, where R^(b1) and R^(c1) optionally form    together with a nitrogen atom to which they are bonded, a 3- to    8-membered cyclic group, where in the cyclic group, one or two    carbon atom(s) is(are) optionally substituted with an atom    optionally selected from an oxygen atom, a sulfur atom, and a    nitrogen atom (the nitrogen atom is optionally substituted with a    C₁₋₆ alkyl group) or with a carbonyl group (with the proviso that    there are excluded a compound which is    5-[4-[2-(2-phenyl-4-oxazolyl)ethoxy]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one;    a compound in which a saturated cyclic amide structure having    —S(O)_(n)—NH—CO— is 1,1-dioxo-1,2-thiazolidin-3-one, the ring B is a    benzene ring, the ring B is bonded to J₁, k is 1, and in the ring B,    a linker moiety containing X and the cyclic amide structure are    positioned at a p-position; and a compound in which the cyclic amide    structure is 1,1-dioxo-1,2,5-thiadiazolidin-3-one, the ring B is    bonded to J₁, and in the ring B, the cyclic amide structure is    bonded to an atom adjacent to an atom to which a linker containing X    is bonded)),    a salt of the compound, or a solvate of the compound or the salt.

Each group in Formula (I) according to Aspect [1] is specificallydescribed below.

In the explanation of the compound according to the present invention,for example, “C₁₋₆” indicates that the number of constituent carbonatoms, which is the number of carbon atoms in a linear, branched, orcyclic group unless otherwise indicated, is 1 to 6. The number ofconstituent carbon atoms includes the total number of carbon atoms in agroup having a linear or branched group substituted with a cyclic groupor a cyclic group substituted with a linear or branched group.Therefore, as for an acyclic group, “C₁₋₆” means a “linear or branchedchain with the number of constituent carbon atoms of 1 to 6”. As for acyclic group, “C₁₋₆” means a “cyclic group with the number ofring-constituting carbon atoms of 1 to 6”. As for a group having anacyclic group and a cyclic group, “C₁₋₆” means a “group with the totalnumber of carbon atoms of 1 to 6”.

The “alkyl group” is a linear, branched, or cyclic alkyl group. Forexample, examples of the “C₁₋₆ alkyl group” include methyl, ethyl,propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl,isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl,1,2-dimethylpropyl, 1-ethylpropyl, hexyl, isohexyl, 1-methylpentyl,2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl,2,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl,3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl,1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl,cyclobutylmethyl, cyclopentylmethyl, 1-cyclopropylethyl,2-cyclopropylethyl, 2-cyclobutylethyl, and 2-methylcyclopropyl. Examplesof the “C₁₋₁₀ alkyl group” include, in addition to the groups mentionedas the “C₁₋₆ alkyl group”, heptyl, 1-methylhexyl, octyl, 2-ethylhexyl,1,1-dimethylhexyl, nonyl, decyl, cycloheptyl, cyclohexylmethyl,2-cyclohexylethyl, 4-methylcyclohexyl, 4,4-dimethylcyclohexyl, and3,3,5,5-tetramethylcyclohexyl. The cyclic alkyl group is also expressedas “cycloalkyl group”. Examples of the “C₅₋₇ cycloalkyl group” includecyclopentyl, cyclohexyl, and cycloheptyl.

The “alkenyl group” is a linear, branched, or cyclic alkenyl group. Forexample, examples of the “C₂₋₆ alkenyl group” include vinyl, allyl,isopropenyl, 2-methylallyl, butenyl, pentenyl, isopentenyl, hexenyl,1-cyclopropen-1-yl, 2-cyclopropen-1-yl, 1-cyclobuten-1-yl,1-cyclopenten-1-yl, 2-cyclopenten-1-yl, 3-cyclopenten-1-yl,1-cyclohexen-1-yl, 2-cyclohexen-1-yl, 3-cyclohexen-1-yl,2,4-cyclopentadien-1-yl, and 2,5-cyclohexadien-1-yl. Examples of the“C₂₋₁₀ alkenyl group” include, in addition to the groups mentioned asthe “C₂₋₆ alkenyl group”, heptenyl, octenyl, nonenyl, decenyl,1-cyclohepten-1-yl, 1-cyclohexen-1-ylmethyl, 4-methyl-1-cyclohexen-1-yl,4,4-dimethyl-1-cyclohexen-1-yl, and3,3,5,5-tetramethyl-1-cyclohexen-1-yl. The cyclic alkenyl group is alsoexpressed as “cycloalkenyl group”. Examples of the “C₅₋₇ cycloalkenylgroup” include 1-cyclopenten-1-yl, 2-cyclopenten-1-yl,3-cyclopenten-1-yl, 1-cyclohexen-1-yl, 2-cyclohexen-1-yl,3-cyclohexen-1-yl, and 1-cyclohepten-1-yl.

The “alkynyl group” is a linear, branched, or cyclic alkynyl group. Forexample, examples of the “C₂₋₆ alkynyl group” include ethynyl,1-propynyl, 2-propynyl, butynyl, pentynyl, and hexynyl. Examples of the“C₂₋₁₀ alkynyl group” include, in addition to the groups mentioned asthe “C₂₋₆ alkynyl group”, heptynyl, octynyl, nonynyl, and decynyl.

The “alkoxy group” is a linear, branched, or cyclic alkoxy group andcomprehensively a group of RO— (as for the C₁₋₆ alkoxy group, R is theC₁₋₆ alkyl group listed above). For example, examples of the “C₁₋₆alkoxy group” include methoxy, ethoxy, propoxy, isopropoxy, butoxy,isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy,neopentyloxy, tert-pentyloxy, 1-methylbutoxy, 2-methylbutoxy,1,2-dimethylpropoxy, 1-ethylpropoxy, hexyloxy, isohexyloxy,1-methylpentyloxy, 2-methylpentyloxy, 3-methylpentyloxy,1,1-dimethylbutyloxy, 1,2-dimethylbutyloxy, 2,2-dimethylbutyloxy,1,3-dimethylbutyloxy, 2,3-dimethylbutyloxy, 3,3-dimethylbutoxy,1-ethylbutyloxy, 2-ethylbutyloxy, 1,1,2-trimethylpropyloxy,1,2,2-trimethylpropyloxy, 1-ethyl-1-methylpropyloxy,1-ethyl-2-methylpropyloxy, cyclopropyloxy, cyclobutyloxy,cyclopentyloxy, cyclohexyloxy, cyclopropylmethoxy, cyclobutylmethoxy,cyclopentylmethoxy, 1-cyclopropylethoxy, 2-cyclopropylethoxy,2-cyclobutylethoxy, and 2-methylcyclopropyloxy. Examples of the “C₁₋₁₀alkoxy group” include, in addition to the groups mentioned as the “C₁₋₆alkoxy group”, heptyloxy, octyloxy, 2-ethylhexyloxy, nonyloxy, decyloxy,cycloheptyloxy, cyclohexylmethoxy, 2-cyclohexylethoxy,4-methylcyclohexyloxy, 4,4-dimethylcyclohexyloxy, and3,3,5,5-tetramethylcyclohexyloxy.

The “alkenyloxy group” is the “alkenyl group” which is substituted withan oxygen atom, denoting a linear, branched, or cyclic alkenyloxy group.For example, examples of the “C₂₋₆ alkenyloxy group” include vinyloxy,allyloxy, isopropenyloxy, 2-methylallyloxy, butenyloxy, pentenyloxy,isopentenyloxy, hexenyloxy, 1-cyclopropen-1-yloxy,2-cyclopropen-1-yloxy, 1-cyclobuten-1-yloxy, 1-cyclopenten-1-yloxy,2-cyclopenten-1-yloxy, 3-cyclopenten-1-yloxy, 1-cyclohexen-1-yloxy,2-cyclohexen-1-yloxy, 3-cyclohexen-1-yloxy, 2,4-cyclopentadien-1-yloxy,and 2,5-cyclohexadien-1-yloxy. Examples of the “C₂₋₁₀ alkenyloxy group”include, in addition to the groups mentioned as the “C₂₋₆ alkenyloxygroup”, heptenyloxy, octenyloxy, nonenyloxy, decenyloxy,1-cyclohepten-1-yloxy, 1-cyclohexen-1-ylmethoxy,4-methyl-1-cyclohexen-1-yloxy, 4,4-dimethyl-1-cyclohexen-1-yloxy, and3,3,5,5-tetramethyl-1-cyclohexen-1-yloxy.

The “alkynyloxy group” is the “alkynyl group” which is substituted withan oxygen atom, denoting a linear, branched, or cyclic alkynyloxy group.For example, examples of the “C₂₋₆ alkynyloxy group” include ethynyloxy,1-propynyloxy, 2-propynyloxy, butynyloxy, pentynyloxy, and hexynyloxy.Examples of the “C₂₋₁₀ alkynyloxy group” include, in addition to thegroups mentioned as the “C₂₋₆ alkynyloxy group”, heptynyloxy,octynyloxy, nonynyloxy, and decynyloxy.

Examples of the “aryl group” include a monocyclic or ring-fused C₆₋₁₄aryl groups, for example, phenyl, 1-naphthyl, 2-naphthyl, anthryl,phenanthryl, and acenaphthyl, or a fused aryl group which is partlyhydrogenated such as (1-, 2-, 4-, or 5-)indanyl, indenyl, andtetrahydronaphthyl. The fused aryl group which is partly hydrogenatedmeans a monovalent group obtained by removing any hydrogen atom from afused ring which is partly hydrogenated, and the hydrogen atom to beremoved is optionally a hydrogen atom in an aromatic ring moiety or ahydrogen atom in a hydrogenated moiety of the fused ring. For example,tetrahydronaphthyl includes 1,2,3,4-tetrahydronaphthalene (-1-yl, -2-yl,-3-yl, -4-yl, -5-yl, -6-yl, -7-yl, -8-yl), and the like.

Examples of the “heterocyclic group” include a “heteroaryl group” and asaturated or unsaturated “non-aromatic heterocyclic group”. The term“cyclic” used for these groups means a monovalent group obtained byremoving any hydrogen atom from a ring having a 3- to 14-membered,preferably a 3- to 12-membered, monocyclic ring or fused ringcontaining, in addition to carbon atoms, at least one (preferably 1 to4) heteroatom(s) optionally selected from N, O, and S.

The “heteroaryl group” can be monocyclic or ring-fused, and themonocyclic heteroaryl group preferably has 5 to 7 ring members andexamples of the “heteroaryl group” include pyrrolyl, furyl, thienyl,imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl,1,3,4-oxadiazolyl, furazanyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,1,3,4-thiadiazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl,pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl,2H-1,2,3-thiadiazinyl, 4H-1,2,4-thiadiazinyl, 6H-1,3,4-thiadiazinyl,1,4-diazepinyl, and 1,4-oxazepinyl.

The ring-fused heteroaryl group preferably has 8 to 14 ring members andincludes a monovalent group obtained by removing any hydrogen atom froma fused ring formed by fusing the 5- to 7-membered heterocyclic ring anda monocyclic aryl group or a monocyclic heteroaryl group, and the like.The hydrogen atom is optionally removed from any of the fused rings.

Specifically, indolyl, isoindolyl, benzofuranyl, isobenzofuranyl,benzothienyl, isobenzothienyl, benzoxazolyl, 1,2-benzisoxazolyl,benzothiazolyl, 1,2-benzisothiazolyl, 1H-benzimidazolyl, 1H-indazolyl,1H-benzotriazolyl, 2,1,3-benzothiadiazinyl, chromenyl, isochromenyl,4H-1,4-benzoxazinyl, 4H-1,4-benzothiazinyl, quinolyl, isoquinolyl,cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, benzoxazepinyl,benzoazepinyl, benzodiazepinyl, naphthyridinyl, purinyl, pteridinyl,carbazolyl, carbolinyl, acridinyl, phenoxazinyl, phenothiazinyl,phenazinyl, phenoxathiinyl, thianthrenyl, phenanthridinyl,phenanthrolinyl, indolizinyl, thieno[3,2-c]pyridyl,thiazolo[5,4-c]pyridyl, pyrrolo[1,2-b]pyridazinyl,pyrazolo[1,5-a]pyridyl, imidazo[1,2-a]pyridyl, imidazo[1,5-a]pyridyl,imidazo[1,2-b]pyridazinyl, imidazo[1,5-a]pyrimidinyl,1,2,4-triazolo[4,3-a]pyridyl, 1,2,4-triazolo[4,3-b]pyridazinyl,1H-pyrazolo[3,4-b]pyridyl, 1,2,4-triazolo[1,5-a]pyrimidinyl,dibenzofuranyl, and the like are mentioned.

In addition, a ring-fused heteroaryl group, etc. which is partlyhydrogenated, such as indolinyl, dihydrobenzofuranyl,dihydroisobenzofuranyl, dihydrobenzoxazolyl, dihydrobenzothiazolyl,chromanyl, isochromanyl, 3,4-dihydro-2H-1,4-benzoxazinyl,3,4-dihydro-2H-1,4-benzothiazinyl, tetrahydroquinolyl,tetrahydroisoquinolyl, tetrahydroquinoxalinyl, 1,3-benzodioxanyl,1,4-benzodioxanyl, 1,3-benzodioxolyl, tetrahydrobenzoxazepinyl,tetrahydrobenzoazepinyl, and 6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridylis mentioned. The ring-fused heteroaryl group, etc. which is partlyhydrogenated is preferably one having 8 to 14 ring members, namely amonovalent group obtained by removing any hydrogen atom from a ringwhich is partly hydrogenated in the fused ring formed by fusing the 5-to 7-membered heterocyclic ring and a monocyclic aryl group or amonocyclic heteroaryl group. The hydrogen atom to be removed isoptionally a hydrogen atom in the aryl group or in the heterocyclicmoiety or a hydrogen atom in the hydrogenated moiety. In the case oftetrahydroquinolyl, examples of the partly hydrogenated ring-fusedheteroaryl group include 5,6,7,8-tetrahydroquinolyl and1,2,3,4-tetrahydroquinolyl. Depending on the position in these groupsfrom which the hydrogen atom is removed, -2-yl, -3-yl, -4-yl, -5-yl,-6-yl, -7-yl, and -8-yl are exemplified in the case of5,6,7,8-tetrahydroquinolyl, and in the case of1,2,3,4-tetrahydroquinolyl, -1-yl, -2-yl, -3-yl, -4-yl, -5-yl, -6-yl,-7-yl, and -8-yl are exemplified.

Examples of the “non-aromatic heterocyclic group” include a 3- to8-membered saturated or unsaturated non-aromatic heterocyclic group, forexample, aziridinyl, azetidinyl, oxiranyl, oxetanyl, thietanyl,pyrrolidinyl, tetrahydrofuryl, thiolanyl, pyrazolinyl, pyrazolidinyl,piperidinyl, dihydropyranyl, tetrahydropyranyl (oxanyl),tetrahydrothiopyranyl, piperazinyl, dioxanyl, oxazolinyl, isoxazolinyl,oxazolidinyl, isoxazolidinyl, thiazolinyl, isothiazolinyl,thiazolidinyl, isothiazolidinyl, oxadiazolinyl, oxadiazolidinyl,morpholinyl, thiomorpholinyl, quinuclidinyl, and oxepanyl, and the“non-aromatic heterocyclic group” means a monovalent group obtained byremoving any hydrogen atom from the ring.

Examples of the “heterocyclic group (the heterocyclic group isoptionally substituted with 1 to 3 C₁₋₆ alkyl group(s) or 1 to 3 oxogroup(s))” include, in addition to the groups mentioned as the“heterocyclic group”, a group in which the cyclic group is substitutedwith 1 to 3 “C₁₋₆ alkyl group(s)” or 1 to 3 oxo group(s) at anyposition. For example, methylpyrrolyl, methylfuryl, methylthienyl,methylimidazolyl, methylpyrazolyl, methyloxazolyl, methylisoxazolyl,methylthiazolyl, methylisothiazolyl, methylpyridyl, methylpyrimidinyl,methylaziridinyl, methylazetidinyl, methyloxiranyl, methyloxetanyl,methylthietanyl, methylpyrrolidinyl, methyltetrahydrofuryl,methylthiolanyl, methylpyrazolinyl, methylpyrazolidinyl,methylpiperidinyl, methyltetrahydropyranyl, methylpiperazinyl,methyloxazolinyl, methylisoxazolinyl, methyloxazolidinyl,methylisoxazolidinyl, methylthiazolinyl, methylisothiazolinyl,methylthiazolidinyl, methylisothiazolidinyl, methyloxadiazolinyl,methyloxadiazolidinyl, methylmorpholinyl, methylthiomorpholinyl,methylquinuclidinyl, methyloxepanyl, oxopyrrolidinyl,1,1-dioxidetetrahydrothiopyranyl, and the like are mentioned.

The “aralkyl group” is a group in which a linear or branched alkyl groupof the “C₁₋₆ alkyl group” is substituted with the “aryl group”, andexamples of the “aralkyl group” include benzyl, phenethyl,3-phenylpropyl, 1-naphthylmethyl, 2-naphthylmethyl, 2-(1-naphthyl)ethyl,2-(2-naphthyl)ethyl, 1-indanylmethyl, 2-indanylmethyl,1,2,3,4-tetrahydronaphthalen-1-ylmethyl, and1,2,3,4-tetrahydronaphthalen-2-ylmethyl.

The “heteroarylalkyl group” is a group in which a linear or branchedalkyl group of the “C₁₋₆ alkyl group” is substituted with the“heteroaryl group”, and examples of the “heteroarylalkyl group” includethose substituted with the “monocyclic heteroaryl group”, such aspyrrolylmethyl, furylmethyl, thienylmethyl, imidazolylmethyl,pyrazolylmethyl, oxazolylmethyl, isoxazolylmethyl, thiazolylmethyl,isothiazolylmethyl, 1,2,3-triazolylmethyl, 1,2,4-triazolylmethyl,1,2,3-oxadiazolylmethyl, 1,2,4-oxadiazolylmethyl,1,3,4-oxadiazolylmethyl, furazanylmethyl, 1,2,3-thiadiazolylmethyl,1,2,4-thiadiazolylmethyl, 1,3,4-thiadiazolylmethyl, tetrazolylmethyl,pyridylmethyl, pyridazinylmethyl, pyrimidinylmethyl, pyrazinylmethyl,1,2,3-triazinylmethyl, 1,2,4-triazinylmethyl, 1,3,5-triazinylmethyl,2H-1,2,3-thiadiazinylmethyl, 4H-1,2,4-thiadiazinylmethyl,6H-1,3,4-thiadiazinylmethyl, 1,4-diazepinylmethyl, and1,4-oxazepinylmethyl, and

those substituted with the “ring-fused heteroaryl group”, such asindolylmethyl, isoindolylmethyl, benzofuranylmethyl,isobenzofuranylmethyl, benzothienylmethyl, isobenzothienylmethyl,benzoxazolylmethyl, 1,2-benzisoxazolylmethyl, benzothiazolylmethyl,1,2-benzisothiazolylmethyl, 1H-benzimidazolylmethyl, 1H-indazolylmethyl,1H-benzotriazolylmethyl, 2,1,3-benzothiadiazinylmethyl, chromenylmethyl,isochromenylmethyl, 4H-1,4-benzoxazinylmethyl,4H-1,4-benzothiazinylmethyl, quinolylmethyl, isoquinolylmethyl,cinnolinylmethyl, quinazolinylmethyl, quinoxalinylmethyl,phthalazinylmethyl, benzoxazepinylmethyl, benzoazepinylmethyl,benzodiazepinylmethyl, naphthyridinylmethyl, purinylmethyl,pteridinylmethyl, carbazolylmethyl, carbolinylmethyl, acridinylmethyl,phenoxazinylmethyl, phenothiazinylmethyl, phenazinylmethyl,phenoxathiinylmethyl, thianthrenylmethyl, phenanthridinylmethyl,phenanthrolinylmethyl, indolizinylmethyl, thieno[3,2-c]pyridylmethyl,thiazolo[5,4-c]pyridylmethyl, pyrrolo[1,2-b]pyridazinylmethyl,pyrazolo[1,5-a]pyridylmethyl, imidazo[1,2-a]pyridylmethyl,imidazo[1,5-a]pyridylmethyl, imidazo[1,2-b]pyridazinylmethyl,imidazo[1,5-a]pyrimidinylmethyl, 1,2,4-triazolo[4,3-a]pyridylmethyl,1,2,4-triazolo[4,3-b]pyridazinylmethyl, 1H-pyrazolo[3,4-b]pyridylmethyl,1,2,4-triazolo[1,5-a]pyrimidinylmethyl, indolinylmethyl,dihydrobenzofuranylmethyl, chromanylmethyl, tetrahydroquinolylmethyl,tetrahydroisoquinolylmethyl, 1,4-benzodioxanylmethyl, and1,3-benzodioxolylmethyl.

The “non-aromatic heterocyclic alkyl group” is a group in which a linearor branched alkyl group of the “C₁₋₆ alkyl group” is substituted withthe “non-aromatic heterocyclic group”, and examples of the “non-aromaticheterocyclic alkyl group” include aziridinylmethyl, azetidinylmethyl,oxiranylmethyl, oxetanylmethyl, thietanylmethyl, pyrrolidinylmethyl,tetrahydrofurylmethyl, thiolanylmethyl, pyrazolinylmethyl,pyrazolidinylmethyl, piperidinylmethyl, dihydropyranylmethyl,tetrahydropyranylmethyl, tetrahydrothiopyranylmethyl, piperazinylmethyl,dioxanylmethyl, oxazolinylmethyl, isoxazolinylmethyl,oxazolidinylmethyl, isoxazolidinylmethyl, thiazolinylmethyl,isothiazolinylmethyl, thiazolidinylmethyl, isothiazolidinylmethyl,oxadiazolinylmethyl, oxadiazolidinylmethyl, morpholinylmethyl,thiomorpholinylmethyl, quinuclidinylmethyl, and oxepanylmethyl.

The “aryloxy group” is the “aryl group” which is substituted with anoxygen atom, and specifically, a group in which the group mentioned asthe “aryl group” is substituted with an oxygen atom is mentioned. Forexample, examples of the “aryloxy group” include phenoxy, 1-naphthyloxy,2-naphthyloxy, 2-anthryloxy, phenanthryloxy, 1-indanyloxy, 2-indanyloxy,1,2,3,4-tetrahydronaphthalen-1-yloxy,1,2,3,4-tetrahydronaphthalen-2-yloxy, and1,2,3,4-tetrahydronaphthalen-8-yloxy.

The “heterocyclic oxy group” is the “heterocyclic group” which issubstituted with an oxygen atom, and a “heteroaryloxy group” or a“non-aromatic heterocyclic oxy group” is mentioned. Specifically, agroup in which the group mentioned as the “heterocyclic group” issubstituted with an oxygen atom is mentioned.

The “heteroaryloxy group” is the “heteroaryl group” which is substitutedwith an oxygen atom, and specifically, a group in which the groupmentioned as the “heteroaryl group” is substituted with an oxygen atomis mentioned. For example, examples of the “heteroaryloxy group” includepyrrolyloxy, furyloxy, thienyloxy, imidazolyloxy, pyrazolyloxy,oxazolyloxy, isoxazolyloxy, thiazolyloxy, isothiazolyloxy, (2-, 3-, or4-)pyridyloxy, pyridazinyloxy, pyrimidinyloxy, pyrazinyloxy, indolyloxy,quinolyloxy, isoquinolyloxy, indolinyloxy, dihydrobenzofuranyloxy,chromanyloxy, tetrahydroquinolyloxy, tetrahydroisoquinolyloxy,1,4-benzodioxanyloxy, and 1,3-benzodioxolyloxy.

The “non-aromatic heterocyclic oxy group” is the “non-aromaticheterocyclic group” which is substituted with an oxygen atom, andspecifically, a group in which the group mentioned as the “non-aromaticheterocyclic group” is substituted with an oxygen atom is mentioned.Examples of the “non-aromatic heterocyclic oxy group” include 3- to8-membered saturated or unsaturated non-aromatic heterocyclic oxy groupssuch as aziridinyloxy, azetidinyloxy, oxiranyloxy, oxetanyloxy,thietanyloxy, pyrrolidinyloxy, tetrahydrofuryloxy, thiolanyloxy,pyrazolinyloxy, pyrazolidinyloxy, (1-, 2-, 3-, or 4-)piperidinyloxy,dihydropyranyloxy, (2-, 3-, or 4-)tetrahydropyranyloxy ((2-, 3-, or4-)oxanyloxy), tetrahydrothiopyranyloxy, piperazinyloxy, dioxanyloxy,oxazolinyloxy, isoxazolinyloxy, oxazolidinyloxy, isoxazolidinyloxy,thiazolinyloxy, isothiazolinyloxy, thiazolidinyloxy,isothiazolidinyloxy, oxadiazolinyloxy, oxadiazolidinyloxy,morpholinyloxy, thiomorpholinyloxy, quinuclidinyloxy, and oxepanyloxy.

Examples of the “heterocyclic oxy group (the heterocyclic oxy group isoptionally substituted with 1 to 3 C₁₋₆ alkyl group(s) or 1 to 3 oxogroup(s))” include, in addition to the groups mentioned as the“heterocyclic oxy group”, a group in which the cyclic group issubstituted with 1 to 3 “C₁₋₆ alkyl group(s)” or 1 to 3 oxo group(s) atany position. The “heterocyclic oxy group” can also be expressed as agroup in which the “heterocyclic group (the heterocyclic group isoptionally substituted with 1 to 3 C₁₋₆ alkyl group(s) or 1 to 3 oxogroup(s))” is substituted with an oxygen atom, and specifically, a groupin which the groups mentioned as the “heterocyclic group (theheterocyclic group is optionally substituted with 1 to 3 C₁₋₆ alkylgroup(s) or 1 to 3 oxo group(s))” are substituted with an oxygen atom,is mentioned.

The “aralkyloxy group” is the “aralkyl group” which is substituted withan oxygen atom, and specifically, a group in which the groups mentionedas the “aralkyl group” are substituted with an oxygen atom is mentioned.For example, examples of the “aralkyloxy group” include benzyloxy,phenethyloxy, 3-phenylpropoxy, 1-naphthylmethoxy, 2-naphthylmethoxy,2-(1-naphthyl)ethoxy, 2-(2-naphthyl)ethoxy, 1-indanylmethoxy,2-indanylmethoxy, 1,2,3,4-tetrahydronaphthalene-1-ylmethoxy, and1,2,3,4-tetrahydronaphthalene-2-ylmethoxy.

The “heteroarylalkyloxy group” is the “heteroarylalkyl group” which issubstituted with an oxygen atom, and specifically, a group in which thegroups mentioned as the “heteroarylalkyl group” are substituted with anoxygen atom is mentioned. For example, a “monocyclic heteroarylalkylgroup” substituted with an oxygen atom, such as pyrrolylmethoxy,furylmethoxy, thienylmethoxy, imidazolylmethoxy, pyrazolylmethoxy,oxazolylmethoxy, isoxazolylmethoxy, thiazolylmethoxy,isothiazolylmethoxy, 1,2,3-triazolylmethoxy, 1,2,4-triazolylmethoxy,1,2,3-oxadiazolylmethoxy, 1,2,4-oxadiazolylmethoxy,1,3,4-oxadiazolylmethoxy, furazanylmethoxy, 1,2,3-thiadiazolylmethoxy,1,2,4-thiadiazolylmethoxy, 1,3,4-thiadiazolylmethoxy, tetrazolylmethoxy,pyridylmethoxy, pyridazinylmethoxy, pyrimidinylmethoxy,pyrazinylmethoxy, 1,2,3-triazinylmethoxy, 1,2,4-triazinylmethoxy,1,3,5-triazinylmethoxy, 2H-1,2,3-thiadiazinylmethoxy,4H-1,2,4-thiadiazinylmethoxy, 6H-1,3,4-thiadiazinylmethoxy,1,4-diazepinylmethoxy, 1,4-oxazepinylmethoxy, and the like, and

a “ring-fused heteroarylalkyl group” which is optionally partlyhydrogenated and is substituted with an oxygen atom, such asindolylmethoxy, isoindolylmethoxy, benzofuranylmethoxy,isobenzofuranylmethoxy, benzothienylmethoxy, isobenzothienylmethoxy,benzoxazolylmethoxy, 1,2-benzisoxazolylmethoxy, benzothiazolylmethoxy,1,2-benzisothiazolylmethoxy, 1H-benzimidazolylmethoxy,1H-indazolylmethoxy, 1H-benzotriazolylmethoxy,2,1,3-benzothiadiazinylmethoxy, chromenylmethoxy, isochromenylmethoxy,4H-1,4-benzoxazinylmethoxy, 4H-1,4-benzothiazinylmethoxy,quinolylmethoxy, isoquinolylmethoxy, cinnolinylmethoxy,quinazolinylmethoxy, quinoxalinylmethoxy, phthalazinylmethoxy,benzoxazepinylmethoxy, benzoazepinylmethoxy, benzodiazepinylmethoxy,naphthyridinylmethoxy, purinylmethoxy, pteridinylmethoxy,carbazolylmethoxy, carbolinylmethoxy, acridinylmethoxy,phenoxazinylmethoxy, phenothiazinylmethoxy, phenazinylmethoxy,phenoxathiinylmethoxy, thianthrenylmethoxy, phenanthridinylmethoxy,phenanthrolinylmethoxy, indolizinylmethoxy, thieno[3,2-c]pyridylmethoxy,thiazolo[5,4-c]pyridylmethoxy, pyrrolo[1,2-b]pyridazinylmethoxy,pyrazolo[1,5-a]pyridylmethoxy, imidazo[1,2-a]pyridylmethoxy,imidazo[1,5-a]pyridylmethoxy, imidazo[1,2-b]pyridazinylmethoxy,imidazo[1,5-a]pyrimidinylmethoxy, 1,2,4-triazolo[4,3-a]pyridylmethoxy,1,2,4-triazolo[4,3-b]pyridazinylmethoxy,1H-pyrazolo[3,4-b]pyridylmethoxy,1,2,4-triazolo[1,5-a]pyrimidinylmethoxy, indolinylmethoxy,dihydrobenzofuranylmethoxy, chromanylmethoxy, tetrahydroquinolylmethoxy,tetrahydroisoquinolylmethoxy, 1,4-benzodioxanylmethoxy,1,3-benzodioxolylmethoxy, and the like, are mentioned.

The “spiro ring group” is a 6- to 18-membered mono spiro-cyclic group inwhich two cyclic groups share one atom as a spiro atom to bespiro-fused. Each cyclic group forming a Spiro ring is a carbon ringgroup (such as a cyclic alkyl group and a partly hydrogenated fused arylgroup) or a heterocyclic group (such as a non-aromatic heterocyclicgroup and a partly hydrogenated ring-fused heteroaryl group) and may bea monocyclic ring or a fused ring. The number of members of the spiroring group is preferably 6 to 14, and when each cyclic group forming thespiro ring is monocyclic, the cyclic groups are independently preferablya 3- to 7-membered cyclic group. Each cyclic group forming the spiroring may independently have, in the ring, 1 to 3 double bond(s),preferably 1 double bond. Examples of the “spiro ring group” includespiro[4,4]nona-(1- or 2-)ene-2-yl, spiro[4,5]dec-(1- or 2-)ene-2-yl,spiro[4,5]dec-(6- or 7-)ene-7-yl, spiro[5,5]undec-2-yl,spiro[5,5]undec-(1- or 2-)ene-2-yl, spiro[inden-1,4′-piperidin]-1′-yl,spiro[indolin-3,4′-piperidin]-1′-yl, andspiro[isobenzofuran-1(3H),4′-piperidin]-1′-yl. These spiro rings areoptionally substituted with, for example, 1 to 5 halogen atom(s), 1 to 5—OH group(s), 1 to 5 C₁₋₆ alkyl group(s), 1 to 5 halogenated C₁₋₆ alkylgroup(s), 1 to 5 C₁₋₆ alkoxy group(s), or 1 to 5 oxo group(s) which maybe the same as or different from each other.

The “substituted spiropiperidinylmethyl group” is a methyl group towhich a substituted spiropiperidinyl group defined by Formula (SP):

(where Rx and Rxa are independently a group selected from a hydrogenatom, a fluorine atom, a chlorine atom, a C₁₋₃ alkyl group, atrifluoromethyl group, and a methoxy group;

-   X₁ is —CH(Ry)CH₂—, —C(Ry)=CH—, —N(Rz)CH₂—, or —C(O)CH₂—;-   Ry is a hydrogen atom or a C₁₋₃ alkyl group; and-   Rz is a hydrogen atom, a C₁₋₃ alkyl group, or a phenyl group) is    bonded,    or a methyl group to which Formula (SP′):

(where R^(6a)s are independently a halogen atom or a C₁₋₃ alkyl group;xa is an integer of 0 to 8; R^(7a) is an oxygen atom or —CH₂—, R^(8a) isan oxygen atom, —CH₂—, or —C(O)—, or R^(7a) and R^(8a) togetheroptionally form —CH═CH— (with the proviso that R^(7a) and R^(8a) are notsimultaneously an oxygen atom); Y^(1a) is ═CR^(9a)— or a nitrogen atom,Y^(2a) is ═CR^(9b)— or a nitrogen atom, Y^(3a) is ═CR^(9c)— or anitrogen atom, and Y^(4a) is ═CR^(9d)— or a nitrogen atom; and R^(9a),R^(9b), R^(9c), and R^(9d) are independently a hydrogen atom, a halogenatom, or a C₁₋₆ alkyl group (with the proviso that 2 or more of Y^(1a)to Y^(4a) are not simultaneously a nitrogen atom))is bonded.

Specifically, the “substituted spiropiperidinylmethyl group” is Formula(SP)—CH₂—:

(where each definition is the same as defined in Formula (SP)), orFormula (SP′)—CH₂—:

(where each definition is the same as defined in Formula (SP′)).

More specific examples of the “substituted spiropiperidinylmethyl group”as Formula (SP)—CH₂— include spiro[indan-1,4′-piperidin]-1′-ylmethyl,(1′H-spiro[inden-1,4′-piperidin]-1′-yl)methyl,1,2-dihydro-1′H-spiro[indol-3,4′-piperidin]-1′-ylmethyl,(1-methyl-1,2-dihydro-1′H-spiro[indol-3,4′-piperidin]-1′-yl)methyl,{1-(1-methylethyl)-1,2-dihydro-1′H-spiro[indol-3,4′-piperidin]-1′-yl}methyl,(1-phenyl-1,2-dihydro-1′H-spiro[indol-3,4′-piperidin]-1′-yl)methyl,(2,3-dihydro-1′H-spiro[inden-1,4′-piperidin]-1′-ylmethyl,(7-chloro-1-methyl-1,2-dihydro-1′H-spiro[indol-3,4′-piperidin]-1′-yl)methyl,(5-fluoro-1-methyl-1,2-dihydro-1′H-spiro[indol-3,4′-piperidin]-1′-yl)methyl,(5-methoxy-1-methyl-1,2-dihydro-1′H-spiro[indol-3,4′-piperidin]-1′-yl)methyl,(1,5-dimethyl-1,2-dihydro-1′H-spiro[indol-3,4′-piperidin]-1′-yl)methyl,[1-methyl-5-(trifluoromethyl)-1,2-dihydro-1′H-spiro[indol-3,4′-piperidin]-1′-yl]methyl,and (3-oxo-2,3-dihydro-1′H-spiro[inden-1,4′-piperidin]-1′-yl)methyl.

As the explanation for the substituted spiropiperidinyl group or theexamples for the substituent in Formula (SP)—CH₂—, the description in WO2011/046851 pamphlet, particularly Formula (3) in p.8 or the structuralformulae and the chemical names in Example 1 to Example 39, and the likecan be referred to.

Specific examples of the “substituted spiropiperidinylmethyl group” asFormula (SP′)—CH₂— include(spiro[isobenzofuran-1(3H),4′-piperidin]-1-yl)methyl,(spiro[benzofuran-3(2H),4′-piperidin]-1-yl)methyl,(3-oxospiro[6-azaisobenzofuran-1(3H),4′-piperidin]-1-yl)methyl,(spiro[5-fluoroisobenzofuran-1(3H),4′-piperidin]-1-yl)methyl,(spiro[6-fluoroisobenzofuran-1(3H),4′-piperidin]-1-yl)methyl,(spiro[5-fluoro-6-azaisobenzofuran-1(3H),4′-piperidin]-1-yl)methyl,(spiro[6-azaisobenzofuran-1(3H),4′-piperidin]-1-yl)methyl,(spiro[5-fluoroisobenzofuran-1(3H),4′-piperidin]-1-yl)methyl,(spiro[6-fluoroisobenzofuran-1(3H),4′-piperidin]-1-yl)methyl,(spiro[5-fluoro-6-azaisobenzofuran-1(3H),4′-piperidin]-1-yl)methyl, and(7-fluoro-1H-spiro[fluoro[3,4-c]pyridin-3,4′-piperidin]-1-yl)methyl.

As the explanation for the substituted spiropiperidinyl group or theexamples for the substituent in Formula (SP′)—CH₂—, each definition,explanation, and Example for a spiropiperidine ring below disclosed asFormula [II] (for the definition for the substituent and the like, eachdefinition in Formula [I] in p.4-5 is to be referred to) in p.9 of WO2002/088989 pamphlet, can be referred to.

(R⁶s are the same as or different from each other and are a halogen atomor a C₁₋₃ alkyl group;

-   x is an integer of 0 or 1 to 8; R⁷ is an oxygen atom or —CH₂—, or R⁷    and R⁸ together form —CH═CH—; R⁸ is an oxygen atom, —CH₂—, or    —C(O)—, or R⁷ and R⁸ together form —CH═CH—, with the proviso that R⁷    and R⁸ are not simultaneously an oxygen atom; Y¹ is ═CR^(9a)— or a    nitrogen atom, Y² is ═CR^(9b)— or a nitrogen atom, Y³ is ═CR^(9c)—    or a nitrogen atom, and Y⁴ is ═CR^(9d)— or a nitrogen atom; and    R^(9a), R^(9b), R^(9c), and R^(9d) are the same as or different from    each other and are a hydrogen atom, a halogen atom, or a C₁₋₆ alkyl    group, with the proviso that 2 or more of Y¹ to Y⁴ are not    simultaneously a nitrogen atom).

Specific examples of the substituted spiropiperidinyl group includespiropiperidines used in Examples of WO 2002/088989 pamphlet and morespecific examples thereof includespiro[isobenzofuran-1(3H),4′-piperidine],spiro[benzofuran-3(2H),4′-piperidine],spiro[6-azaisobenzofuran-1(3H),4′-piperidine],3-oxospiro[4-azaisobenzofuran-1(3H),4′-piperidine], and3-oxospiro[6-azaisobenzofuran-1(3H),4′-piperidine].

As the subordinate concept of the spiropiperidines disclosed in WO2002/088989 pamphlet and as specific examples for the halogenatedspiropiperidine ring, further, Examples in EP 1595867 and WO 2011/037771pamphlet can be referred to. More specific examples of the substitutedspiropiperidinyl group includespiro[5-fluoroisobenzofuran-1(3H),4′-piperidine],spiro[6-fluoroisobenzofuran-1(3H),4′-piperidine],spiro[5-fluoro-6-azaisobenzofuran-1(3H),4′-piperidine],spiro[6-fluoro-5-azaisobenzofuran-1(3H),4′-piperidine], and7-fluoro-1H-spiro[fluoro[3,4-c]pyridin-3,4′-piperidine.

In the present invention, as a preferred aspect of various compoundshaving a substituted spiropiperidinyl group of Formula (SP′) as asubstructure: xa is preferably 0; R^(7a) and R^(8a) together form—R^(7a)—R^(8a)— which is any one of —OCH₂—, —CH₂O—, —CH₂—CH₂—, —CH═CH—,and —OC(O)—, more preferably —OCH₂— or —CH₂—CH₂—; Y^(1a) is ═CR^(9a)— ora nitrogen atom, Y^(2a) is ═CR^(9b)— or a nitrogen atom, Y^(3a) is═CR^(9c)— or a nitrogen atom, and Y^(4a) is ═CR^(9d)— or a nitrogenatom; and R^(9a), R^(9b), R^(9c), and R^(9d) are independently ahydrogen atom, a halogen atom, or a C₁₋₆ alkyl group (with the provisothat 2 or more of Y^(1a) to Y^(4a) are not simultaneously a nitrogenatom).

Examples of the “halogen atom” include a fluorine atom, a chlorine atom,a bromine atom, and an iodine atom.

The “halogenated C₁₋₆ alkyl group” is a group in which the “C₁₋₆ alkylgroup” is optionally substituted with 1 to 5 halogen atom(s). Forexample, trifluoromethyl, trifluoroethyl, tetrafluoroethyl,pentafluoroethyl, and the like are mentioned.

The “halogenated C₁₋₆ alkoxy” is a group in which the “C₁₋₆ alkoxy” isoptionally substituted with 1 to 5 halogen atom(s). For example,trifluoromethoxy, trifluoroethoxy, tetrafluoroethoxy, pentafluoroethoxy,and the like are mentioned.

Examples of the protective group for the “carboxy which is optionallyprotected” include: an alkyl ester-based protective group such asmethyl, ethyl, tert-butyl, benzyl, diphenylmethyl, and trityl; and asilyl ester-based protective group such as trimethylsilyl andtert-butyldimethylsilyl.

The “C₂₋₇ alkanoyl group” means a “linear, branched, or cyclic C₂₋₇alkylcarbonyl group” and is expressed as R—CO— (R is the “C₁₋₆ alkylgroup”). Examples thereof include acetyl, propionyl, butyryl,isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, heptanoyl,cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl,cyclohexylcarbonyl, cyclopropylmethylcarbonyl, and2-methylcyclopropylcarbonyl.

Examples of the “C₂₋₇ alkanoyl group (the alkanoyl group is optionallysubstituted with —OH or a C₁₋₆ alkoxy group)” include, in addition tothe groups mentioned as the “C₂₋₇ alkanoyl group”, a group in which thealkanoyl group is substituted with —OH or a C₁₋₆ alkoxy group at anyposition and specific examples thereof include hydroxyacetyl andmethoxyacetyl.

The “arylcarbonyl group” is a group in which a carbonyl group is bondedto the “aryl group”, and examples thereof include C₆₋₁₄ arylcarbonylsuch as benzoyl and naphthylcarbonyl.

The “heterocyclic carbonyl group” means a “heterocyclic carbonyl group”,and examples thereof include the “heterocyclic group” (for example, aheteroaryl group, a saturated or unsaturated non-aromatic heterocyclicgroup, and the like) to which a carbonyl group is bonded, including acarbonyl group to which the “monocyclic heteroaryl group” is bonded,such as pyrrolylcarbonyl, furylcarbonyl, thienylcarbonyl,imidazolylcarbonyl, pyrazolylcarbonyl, oxazolylcarbonyl,isoxazolylcarbonyl, thiazolylcarbonyl, isothiazolylcarbonyl,1,2,3-triazolylcarbonyl, 1,2,4-triazolylcarbonyl,1,2,3-oxadiazolylcarbonyl, 1,2,4-oxadiazolylcarbonyl,1,3,4-oxadiazolylcarbonyl, furazanylcarbonyl,1,2,3-thiadiazolylcarbonyl, 1,2,4-thiadiazolylcarbonyl,1,3,4-thiadiazolylcarbonyl, tetrazolylcarbonyl, pyridylcarbonyl,pyridazinylcarbonyl, pyrimidinylcarbonyl, pyrazinylcarbonyl,1,2,3-triazinylcarbonyl, 1,2,4-triazinylcarbonyl,1,3,5-triazinylcarbonyl, 2H-1,2,3-thiadiazinylcarbonyl,4H-1,2,4-thiadiazinylcarbonyl, 6H-1,3,4-thiadiazinylcarbonyl,1,4-diazepinylcarbonyl, and 1,4-oxazepinylcarbonyl; a carbonyl group towhich the “ring-fused heteroaryl group” which is optionally partlyhydrogenated is bonded, such as indolylcarbonyl, isoindolylcarbonyl,benzofuranylcarbonyl, isobenzofuranylcarbonyl, benzothienylcarbonyl,isobenzothienylcarbonyl, benzoxazolylcarbonyl,1,2-benzisoxazolylcarbonyl, benzothiazolylcarbonyl,1,2-benzisothiazolylcarbonyl, 1H-benzimidazolylcarbonyl,1H-indazolylcarbonyl, 1H-benzotriazolylcarbonyl,2,1,3-benzothiadiazinylcarbonyl, chromenylcarbonyl,isochromenylcarbonyl, 4H-1,4-benzoxazinylcarbonyl,4H-1,4-benzothiazinylcarbonyl, quinolylcarbonyl, isoquinolylcarbonyl,cinnolinylcarbonyl, quinazolinylcarbonyl, quinoxalinylcarbonyl,phthalazinylcarbonyl, benzoxazepinylcarbonyl, benzoazepinylcarbonyl,benzodiazepinylcarbonyl, naphthyridinylcarbonyl, purinylcarbonyl,pteridinylcarbonyl, carbazolylcarbonyl, carbolinylcarbonyl,acridinylcarbonyl, phenoxazinylcarbonyl, phenothiazinylcarbonyl,phenazinylcarbonyl, phenoxathiinylcarbonyl, thianthrenylcarbonyl,phenanthridinylcarbonyl, phenanthrolinylcarbonyl, indolizinylcarbonyl,thieno[3,2-c]pyridylcarbonyl, thiazolo[5,4-c]pyridylcarbonyl,pyrrolo[1,2-b]pyridazinylcarbonyl, pyrazolo[1,5-a]pyridylcarbonyl,imidazo[1,2-a]pyridylcarbonyl, imidazo[1,5-a]pyridylcarbonyl,imidazo[1,2-b]pyridazinylcarbonyl, imidazo[1,5-a]pyrimidinylcarbonyl,1,2,4-triazolo[4,3-a]pyridylcarbonyl,1,2,4-triazolo[4,3-b]pyridazinylcarbonyl,1H-pyrazolo[3,4-b]pyridylcarbonyl,1,2,4-triazolo[1,5-a]pyrimidinylcarbonyl, indolinylcarbonyl,dihydrobenzofuranylcarbonyl, chromanylcarbonyl,tetrahydroquinolylcarbonyl, tetrahydroisoquinolylcarbonyl,1,4-benzodioxanylcarbonyl, and 1,3-benzodioxolylcarbonyl, and

a carbonyl group to which the “saturated or unsaturated non-aromaticheterocyclic group” is bonded, such as aziridinylcarbonyl,azetidinylcarbonyl, pyrrolidinylcarbonyl, tetrahydrofurylcarbonyl,piperidinylcarbonyl, tetrahydropyranylcarbonyl, piperazinylcarbonyl, andmorpholinylcarbonyl.

The “non-aromatic heterocyclic carbonyl group” is the “heterocycliccarbonyl group” in which the “heterocyclic group” is a “non-aromaticheterocyclic group”, that is, a group in which a carbonyl group isbonded to the “non-aromatic heterocyclic group”. Specifically, acarbonyl group to which the “saturated or unsaturated non-aromaticheterocyclic group” mentioned as the “heterocyclic carbonyl group” isbonded is mentioned.

In the “—COOR^(f) group”, R^(f) is a hydrogen atom or a C₁₋₆ alkyl groupand means a carboxy group or an alkoxycarbonyl group. Specifically, forexample, carboxy, methoxycarbonyl, ethoxycarbonyl, and the like arementioned.

In the “—S(O)_(i)R^(a) group”, i is an integer of 0 to 2, and R^(a) is agroup optionally selected from a C₁₋₆ alkyl group and a halogenated C₁₋₆alkyl group. When i is 0, examples of the “—S(O)_(i)R^(a) group” includea “C₁₋₆ alkylthio group” and a “halogenated C₁₋₆ alkylthio group”, wheni is 1, examples of the “—S(O)_(i)R^(a) group” include a “C₁₋₆alkylsulfinyl group” and a “halogenated C₁₋₆ alkylsulfinyl group”, andwhen i is 2, examples of the “—S(O)_(i)R^(a) group” include a “C₁₋₆alkylsulfonyl group” and a “halogenated C₁₋₆ alkylsulfonyl group”.

The “C₁₋₆ alkylthio group” means a linear, branched, or cyclic C₁₋₆alkylthio group, and examples thereof include methylthio, ethylthio,propylthio, isopropylthio, butylthio, isobutylthio, sec-butylthio,tert-butylthio, pentylthio, isopentylthio, neopentylthio,tert-pentylthio, 1-methylbutylthio, 2-methylbutylthio,1,2-dimethylpropylthio, 1-ethylprnpylthio, hexylthio, isohexylthio,1-methylpentylthio, 2-methylpentylthio, 3-methylpentylthio,1,1-dimethylbutylthio, 1,2-dimethylbutylthio, 2,2-dimethylbutylthio,1,3-dimethylbutylthio, 2,3-dimethylbutylthio, 3,3-dimethylbutylthio,1-ethylbutylthio, 2-ethylbutylthio, 1,1,2-trimethylpropylthio,1,2,2-trimethylpropylthio, 1-ethyl-1-methylpropylthio,1-ethyl-2-methylpropylthio, cyclopropylthio, cyclobutylthio,cyclopentylthio, cyclohexylthio, cyclopropylmethylthio,cyclobutylmethylthio, cyclopentylmethylthio, 1-cyclopropylethylthio,2-cyclopropylethylthio, 2-cyclobutylethylthio, and2-methylcyclopropylthio. The “halogenated C₁₋₆ alkylthio group” is agroup in which the “C₁₋₆ alkylthio group” is optionally substituted with1 to 5 halogen atom(s), and examples thereof includetrifluoromethylthio.

The “C₁₋₆ alkylsulfinyl group” means a linear, branched, or cyclic C₁₋₆alkylsulfinyl group, and examples thereof include methylsulfinyl,ethylsulfinyl, propylsulfinyl, isopropylsulfinyl, cyclopropylsulfinyl,cyclopropylmethylsulfinyl, and 2-methylcyclopropylsulfinyl. The“halogenated C₁₋₆ alkylsulfinyl group” is a group in which the “C₁₋₆alkylsulfinyl group” is optionally substituted with 1 to 5 halogenatom(s), and examples thereof include trifluoromethylsulfinyl.

The “C₁₋₆ alkylsulfonyl group” means a linear, branched, or cyclic C₁₋₆alkylsulfonyl group, and examples thereof include methylsulfonyl,ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, cyclopropylsulfonyl,cyclopropylmethylsulfonyl, and 2-methylcyclopropylsulfonyl. The“halogenated C₁₋₆ alkylsulfonyl group” is a group in which the “C₁₋₆alkylsulfonyl group” is optionally substituted with 1 to 5 halogenatom(s), and examples thereof include trifluoromethylsulfonyl.

The “—SO₂NR^(d)R^(e) group”, in which R^(d) and R^(e) are independentlya hydrogen atom or a C₁₋₆ alkyl group (the C₁₋₆ alkyl group isoptionally substituted with 1 to 5 halogen atom(s), 1 to 5 —OH, or 1 to5 C₁₋₆ alkoxy group(s)), means, in addition to a sulfamoyl group inwhich 1 or 2 hydrogen atom(s) on a nitrogen atom of the sulfamoyl groupis(are) optionally substituted with the “C₁₋₆ alkyl group”, a sulfamoylgroup substituted with a C₁₋₆ alkyl group (the C₁₋₆ alkyl group isoptionally substituted with 1 to 5 halogen atom(s), 1 to 5 —OH, or 1 to5 C₁₋₆ alkoxy group(s)). Specifically, for example, a sulfamoyl group, amethylsulfamoyl group, an ethylsulfamoyl group, a propylsulfamoyl group,an isopropylsulfamoyl group, a cyclopropylsulfamoyl group, abutylsulfamoyl group, an isobutylsulfamoyl group, a pentylsulfamoylgroup, an isopentylsulfamoyl group, a hexylsulfamoyl group, anisohexylsulfamoyl group, a dimethylsulfamoyl group, a diethylsulfamoylgroup, a dipropylsulfamoyl group, a di-isopropylsulfamoyl group, adibutylsulfamoyl group, a dipentylsulfamoyl group, anethylmethylsulfamoyl group, a methylpropylsulfamoyl group, anethylpropylsulfamoyl group, a butylmethylsulfamoyl group, abutylethylsulfamoyl group, a butylpropylsulfamoyl group, atrifluoromethylsulfamoyl group, a hydroxymethylsulfamoyl group, a2-hydroxyethylsulfamoyl group, a 3-hydroxypropylsulfamoyl group, a3-hydroxybutylsulfamoyl group, a 3-hydroxy-3-methylbutylsulfamoyl group,a 2,3-dihydroxypropylsulfamoyl group, a3-hydroxy-2-hydroxymethylpropylsulfamoyl group, a3-hydroxy-2-hydroxymethyl-2 methylpropylsulfamoyl group, a2-methoxyethylsulfamoyl group, a 2-ethoxyethylsulfamoyl group, a2-methoxy-3-hydroxypropylsulfamoyl group, and the like are mentioned.

The “—CONR^(d)R^(e) group”, in which R^(d) and R^(e) are independently ahydrogen atom or a C₁₋₆ alkyl group (the C₁₋₆ alkyl group is optionallysubstituted with 1 to 5 halogen atom(s), 1 to 5 —OH, or 1 to 5 C₁₋₆alkoxy group(s)), means, in addition to a carbamoyl group in which 1 or2 hydrogen atom(s) on a nitrogen atom of the carbamoyl group is(are)optionally substituted with the “C₁₋₆ alkyl group”, a carbamoyl groupsubstituted with a C₁₋₆ alkyl group (the C₁₋₆ alkyl group is optionallysubstituted with 1 to 5 halogen atom(s), 1 to 5 —OH, or 1 to 5 C₁₋₆alkoxy group(s)). Specifically, for example, a carbamoyl group, amethylcarbamoyl group, an ethylcarbamoyl group, a propylcarbamoyl group,an isopropylcarbamoyl group, a cyclopropylcarbamoyl group, abutylcarbamoyl group, an isobutylcarbamoyl group, a pentylcarbamoylgroup, an isopentylcarbamoyl group, a hexylcarbamoyl group, anisohexylcarbamoyl group, a dimethylcarbamoyl group, a diethylcarbamoylgroup, a dipropylcarbamoyl group, a di-isopropylcarbamoyl group, adibutylcarbamoyl group, a dipentylcarbamoyl group, anethylmethylcarbamoyl group, a methylpropylcarbamoyl group, anethylpropylcarbamoyl group, a butylmethylcarbamoyl group, abutylethylcarbamoyl group, a butylpropylcarbamoyl group, atrifluoromethylcarbamoyl group, a hydroxymethylcarbamoyl group, a2-hydroxyethylcarbamoyl group, a 3-hydroxypropylcarbamoyl group, a3-hydroxybutylcarbamoyl group, a 3-hydroxy-3-methylbutylcarbamoyl group,a 2,3-dihydroxypropylcarbamoyl group, a3-hydroxy-2-hydroxymethylpropylcarbamoyl group, a3-hydroxy-2-hydroxymethyl-2 methylpropylcarbamoyl group, a2-methoxyethylcarbamoyl group, a 2-ethoxyethylcarbamoyl group, a2-methoxy-3-hydroxypropylcarbamoyl group, and the like are mentioned.

In the “—CONR^(d)R^(e1) group”, R^(d) is a hydrogen atom or a C₁₋₆ alkylgroup (the C₁₋₆ alkyl group is optionally substituted with 1 to 5halogen atom(s), 1 to 5 —OH, or 1 to 5 C₁₋₆ alkoxy group(s)), and R^(e1)is a C₁₋₆ alkyl group (the C₁₋₆ alkyl group is substituted with 1 to 5—OH, 1 to 5 C₁₋₆ alkoxy group(s), 1 to 5 aryl group(s) (the aryl groupis optionally substituted with 1 to 3 halogen atom(s)), 1 to 5heterocyclic group(s) (the heterocyclic group is optionally substitutedwith 1 to 3 C₁₋₆ alkyl groups) or 1 to 3 oxo group(s)), 1 to5—S(O)_(i)R^(a) group(s) (i is an integer of 0 to 2), 1 to 5—SO₂NR^(d)R^(e) group(s), 1 to 5 —CONR^(d)R^(e) group(s), or 1 to 5—NR^(b1)R^(c1) group(s). That is to say, the “—CONR^(d)R^(e1) group”means, in addition to a carbamoyl group in which one hydrogen atom on anitrogen atom of the carbamoyl group is substituted with R^(e1), acarbamoyl group in which another hydrogen atom on the nitrogen atom ofthe carbamoyl group is substituted with a C₁₋₆ alkyl group (the C₁₋₆alkyl group is optionally substituted with 1 to 5 halogen atom(s), 1 to5 —OH, or 1 to 5 C₁₋₆ alkoxy group(s)). Specifically, for example, ahydroxymethylcarbamoyl group, a 2-hydroxyethylcarbamoyl group, a3-hydroxypropylcarbamoyl group, a 3-hydroxybutylcarbamoyl group, a3-hydroxy-3-methylbutylcarbamoyl group, a 2,3-dihydroxypropylcarbamoylgroup, a 3-hydroxy-2-hydroxymethylpropylcarbamoyl group, a3-hydroxy-2-hydroxymethyl-2 methylpropylcarbamoyl group, a2-methoxyethylcarbamoyl group, a 2-ethoxyethylcarbamoyl group, a2-methoxy-3-hydroxypropylcarbamoyl group, a3-methylsulfonyl-propylcarbamoyl group, a2-(morpholin-4-yl)ethylcarbamoyl group, a2-(4-methylpiperazin-1-yl)ethylcarbamoyl group, a2-(2-oxopyrrolidin-1-yl)ethylcarbamoyl group, a3-(2-oxopyrrolidin-1-yl)propylcarbamoyl group, a(5-oxopyrrolidin-2-yl)methylcarbamoyl group, a3-(2-oxooxazolidin-3-yl)propylcarbamoyl group, a(3-methyloxetan-3-yl)methylcarbamoyl group, a3-(methylsulfonylamino)propylcarbamoyl group, and the like arementioned.

In the “—NR^(b)R^(c) group”, R^(b) and R^(c) are independently a groupoptionally selected from a hydrogen atom, a C₁₋₆ alkyl group, ahalogenated C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, a C₂₋₆ alkynylgroup, a C₂₋₇ alkanoyl group (the alkanoyl group is optionallysubstituted with —OH or a C₁₋₆ alkoxy group), a C₁₋₆ alkylsulfonylgroup, an arylcarbonyl group, and a heterocyclic carbonyl group. R^(b)and R^(c) optionally form, together with a nitrogen atom to which theyare bonded, a 3- to 8-membered cyclic group, where in the cyclic group,one or two carbon atom(s) is(are) optionally substituted with an atomoptionally selected from an oxygen atom, a sulfur atom, and a nitrogenatom (the nitrogen atom is optionally substituted with a C₁₋₆ alkylgroup which is optionally substituted with 1 to 5 substituent(s) RI) orwith a carbonyl group, and the cyclic group is optionally furthersubstituted with 1 to 5 substituent(s) RII. Examples of the“—NR^(b)R^(c) group” include amino, “mono/di C₁₋₆ alkylamino”,“halogenated mono/di C₁₋₆ alkylamino”, “mono/di C₂₋₆ alkenylamino”,“mono/di C₂₋₆ alkynylamino”, “C₂₋₇ alkanoylamino which is optionallysubstituted with —OH or C₁₋₆ alkoxy”, “C₁₋₆ alkylsulfonylamino”,“arylcarbonylamino”, and “heterocyclic carbonylamino”.

In the “—NR^(b1)R^(c1) group”, R^(b1) and R^(c1) are independently agroup optionally selected from a hydrogen atom, a C₁₋₆ alkyl group, aC₂₋₇ alkanoyl group, and a C₁₋₆ alkylsulfonyl group. R^(b1) and R^(c1)optionally form, together with a nitrogen atom to which they are bonded,a 3- to 8-membered cyclic group, where in the cyclic group, one carbonatom is optionally substituted with an atom optionally selected from anoxygen atom, a sulfur atom, and a nitrogen atom (the nitrogen atom isoptionally substituted with a C₁₋₆ alkyl group) or with a carbonylgroup. Examples of the “—NR^(b1)R^(c1) group” include amino, “mono/diC₁₋₆ alkylamino”, “C₂₋₇ alkanoylamino”, and “C₁₋₆ alkylsulfonylamino”.

The “mono/di C₁₋₆ alkylamino” means an amino group, 1 or 2 hydrogenatom(s) of which is(are) substituted with a linear, branched, or cyclic“C₁₋₆ alkyl group”. Specifically, methylamino, ethylamino, propylamino,isopropylamino, butylamino, isobutylamino, pentylamino, isopentylamino,hexylamino, isohexylamino, cyclopropylamino, cyclobutylamino,cyclopentylamino, cyclohexylamino, 1-cyclopropylmethylamino,1-cyclobutylmethylamino, 1-cyclopentylmethylamino,1-cyclohexylmethylamino, dimethylamino, diethylamino, dipropylamino,diisopropylamino, dibutylamino, dipentylamino, ethylmethylamino,propylmethylamino, propylethylamino, butylmethylamino, butylethylamino,butylpropylamino, N-cyclopropyl-N-methylamino,N-cyclobutyl-N-methylamino, N-cyclopentyl-N-methylamino,N-cyclohexyl-N-methylamino, and the like are mentioned.

The “halogenated mono/di C₁₋₆ alkylamino” is a group in which the“mono/di C₁₋₆ alkylamino” is substituted with 1 to 5 halogen atom(s).For example, trifluoromethylamino and the like are mentioned.

The “mono/di C₂₋₆ alkenylamino” means an amino group, 1 or 2 hydrogenatom(s) of which is(are) substituted with a linear, branched, or cyclic“C₂₋₆ alkenyl group”. Specifically, vinylamino, allylamino,isopropenylamino, 2-methylallylamino, butenylamino, pentenylamino,hexenylamino, 1-cyclopropen-1-ylamino, 2-cyclopropen-1-ylamino,1-cyclobuten-1-ylamino, 1-cyclopenten-1-ylamino,2-cyclopenten-1-ylamino, 3-cyclopenten-1-ylamino,1-cyclohexen-1-ylamino, 2-cyclohexen-1-ylamino, 3-cyclohexen-1-ylamino,2,4-cyclopentadien-1-ylamino, 2,5-cyclohexadien-1-ylamino, divinylamino,diallylamino, diisopropenylamino, di(2-methylallyl)amino,dibutenylamino, dipentenylamino, dihexenylamino,di(1-cyclopropen-1-yl)amino, di(2-cyclopropen-1-yl)amino,di(1-cyclobuten-1-yl)amino, di(1-cyclopenten-1-yl)amino,di(2-cyclopenten-1-yl)amino, di(3-cyclopenten-1-yl)amino,di(1-cyclohexen-1-yl)amino, di(2-cyclohexen-1-yl)amino,di(3-cyclohexen-1-yl)amino, di(2,4-cyclopentadien-1-yl)amino,di(2,5-cyclohexadien-1-yl)amino, and the like are mentioned.

The “mono/di C₂₋₆ alkynylamino” means an amino group, 1 or 2 hydrogenatom(s) of which is(are) substituted with a linear, branched, or cyclic“C₂₋₆ alkynyl group”. Specifically, ethynylamino, 1-propynylamino,2-propynylamino, butynylamino, pentynylamino, hexynylamino,diethynylamino, di(1-propynyl)amino, di(2-propynyl)amino,dibutynylamino, dipentynylamino, dihexynylamino, and the like arementioned.

The “C₂₋₇ alkanoylamino which is optionally substituted with —OH or C₁₋₆alkoxy” means an amino group, a hydrogen atom of which is substitutedwith a linear, branched, or cyclic “C₂₋₇ alkanoyl group (the alkanoylgroup is optionally substituted with —OH or a C₁₋₆ alkoxy group)”.Specifically, acetamide, propionamide, butylamide, isobutylamide,valeramide, isovaleramide, pivalamide, hexanamide, heptanamide,cyclopropanecarboxamide, cyclobutanecarboxamide,cyclopentanecarboxamide, cyclohexanecarboxamide,2-methylcyclopropanecarboxamide, hydroxyacetylamino, methoxyacetylamino,and the like are mentioned.

The “C₁₋₆ alkylsulfonylamino” means an amino group, a hydrogen atom ofwhich is substituted with a linear, branched, or cyclic C₁₋₆alkylsulfonyl group. Specifically, methylsulfonylamino,ethylsulfonylamino, propylsulfonylamino, isopropylsulfonylamino,cyclopropylsulfonylamino, cyclopropylmethylsulfonylamino,2-methylcyclopropylsulfonylamino, and the like are mentioned.

The “arylcarbonylamino” means an amino group, a hydrogen atom of whichis substituted with the “arylcarbonyl group”. Specifically, C₆₋₁₄arylcarbonylamino such as benzamide and naphthamide is mentioned.

The “heterocyclic carbonylamino” means an amino group, a hydrogen atomof which is substituted with the “heterocyclic carbonyl group”.Specifically, pyrrolecarboxamide, furancarboxamide,thiophenecarboxamide, imidazolecarboxamide, pyrazolecarboxamide,pyridinecarboxamide, indolecarboxamide, quinolinecarboxamide,piperidinecarboxamide, and the like are mentioned.

With regard to “R^(b) and R^(c) optionally form, together with anitrogen atom to which they are bonded, a 3- to 8-membered cyclic group”and “R^(b1) and R^(c1) optionally form, together with a nitrogen atom towhich they are bonded, a 3- to 8-membered cyclic group”, the 3- to8-membered cyclic group specifically means, for example, a monovalentcyclic group obtained by removing a hydrogen atom which is bonded to anitrogen atom from a ring that has a nitrogen atom in addition to carbonatoms in a 3- to 8-membered saturated or unsaturated non-aromaticheterocyclic group that is one of the “non-aromatic heterocyclicgroups”. For example, aziridinyl, azetidinyl, pyrrolidinyl, pyrazolinyl,pyrazolidinyl, piperidinyl, piperazinyl, oxazolinyl, isoxazolinyl,oxazolidinyl, isoxazolidinyl, thiazolinyl, isothiazolinyl,thiazolidinyl, isothiazolidinyl, oxadiazolinyl, oxadiazolidinyl,morpholinyl, thiomorpholinyl, 2-oxopyrrolidinyl, and the like arementioned. As for R^(b) and R^(c), and R^(b1) and R^(c1), with regard to“where in the cyclic group, one carbon atom is substituted with anoxygen atom, a sulfur atom, or a carbonyl group”, examples of the cyclicgroup include, among the above-mentioned cyclic groups, oxazolinyl,isoxazolinyl, oxazolidinyl, isoxazolidinyl, thiazolinyl, isothiazolinyl,thiazolidinyl, isothiazolidinyl, morpholinyl, thiomorpholinyl, and2-oxopyrrolidinyl.

As for R^(b) and R^(c), with regard to “where the nitrogen atom issubstituted with a C₁₋₆ alkyl group which is optionally substituted with1 to 5 substituent(s) RI”, examples of the cyclic group include4-methylpiperazin-1-yl, 4-ethylpiperazin-1-yl, 4-propylpiperazin-1-yl,and 4-trifluoromethylpiperazin-1-yl.

As for R^(b1) and R^(c1), with regard to “where the nitrogen atom issubstituted with a C₁₋₆ alkyl group”, examples of the cyclic groupinclude 4-methylpiperazin-1-yl, 4-ethylpiperazin-1-yl, and4-propylpiperazin-1-yl.

As for R^(b) and R^(c), with regard to “where the cyclic group isfurther substituted with 1 to 5 substituent(s) RII”, examples of thecyclic group include 4,4-difluoropiperidin-1-yl.

The “substituent RI” is a group optionally selected from a halogen atom,—OH, a cyano group, a C₁₋₆ alkoxy group (the C₁₋₆ alkoxy group isoptionally substituted with 1 to 5 halogen atom(s), 1 to 5 —OH, 1 to 5C₁₋₆ alkoxy group(s), 1 to 5 aryl group(s) (the aryl group is optionallysubstituted with 1 to 3 halogen atom(s)), 1 to 5 heterocyclic group(s)(the heterocyclic group is optionally substituted with 1 to 3 C₁₋₆ alkylgroup(s) or 1 to 3 oxo group(s)), 1 to 5 —S(O)_(i)R^(a) (i is an integerof 0 to 2) group(s), 1 to 5—SO₂NR^(d)R^(e) group(s), 1 to 5—CONR^(d)R^(e) group(s), or 1 to 5 —NR^(b1)R^(c1) group(s)), a—NR^(b1)R^(c1) group, and a heterocyclic oxy group (the heterocyclic oxygroup is optionally substituted with 1 to 3 C₁₋₆ alkyl group(s) or 1 to3 oxo group(s)).

The “substituent RII” is a group optionally selected from the samegroups as in the case of the “substituent RI”, a C₁₋₆ alkyl group (theC₁₋₆ alkyl group is optionally substituted with 1 to 5 halogen atom(s),1 to 5 —OH, 1 to 5 C₁₋₆ alkoxy group(s), 1 to 5—S(O)_(i)R^(a) (i is aninteger of 0 to 2) group(s), 1 to 5 —NR^(b1)R^(c1) group(s), 1 to 5—SO₂NR^(d)R^(e) group(s), or 1 to 5 —CONR^(d)R^(e) group(s)), a C₂₋₆alkenyl group, a C₂₋₇ alkanoyl group, an aralkyloxy group, aheterocyclic group (the heterocyclic group is optionally substitutedwith 1 to 3 C₁₋₆ alkyl group(s) or 1 to 3 oxo group(s)), a heterocycliccarbonyl group (the heterocyclic carbonyl group is optionallysubstituted with 1 to 3 C₁₋₆ alkyl group(s) or 1 to 3 oxo group(s)), a—S(O)_(i)R^(a) (i is an integer of 0 to 2) group, a —CONR^(d)R^(e)group, and a —CONR^(d)R^(e1) group.

Here, R^(a), R^(d), R^(e), R^(b1), R^(c1), and R^(e1) are the same asdefined above as R^(a), R^(d), R^(e), R^(b1), R^(c1), and R^(e1)respectively in the “—S(O)_(i)R^(a) group”, the “—SO₂NR^(d)R^(e) group”,the “—CONR^(d)R^(e) group”, the “—CONR^(d)R^(e1) group”, and the“—NR^(b1)R^(c1) group”.

The “C₁₋₆ alkyl group which is optionally substituted with 1 to 5substituent(s) RI” is a “C₁₋₆ alkyl group which is optionallysubstituted with 1 to 5 group(s) optionally selected from a halogenatom, —OH, a cyano group, a C₁₋₆ alkoxy group (the C₁₋₆ alkoxy group isoptionally substituted with 1 to 5 halogen atom(s), 1 to 5 —OH, 1 to 5C₁₋₆ alkoxy group(s), 1 to 5 aryl group(s) (the aryl group is optionallysubstituted with 1 to 3 halogen atom(s)), 1 to 5 heterocyclic group(s)(the heterocyclic group is optionally substituted with 1 to 3 C₁₋₆ alkylgroup(s) or 1 to 3 oxo group(s)), 1 to 5 —S(O)_(i)R^(a) (i is an integerof 0 to 2) group(s), 1 to 5 —NR^(b1)R^(c1) group(s), 1 to 5—SO₂NR^(d)R^(e) group(s), or 1 to 5 —CONR^(d)R^(e) group(s)), a—NR^(b1)R^(c1) group, and a heterocyclic oxy group (the heterocyclic oxygroup is optionally substituted with 1 to 3 C₁₋₆ alkyl group(s) or 1 to3 oxo group(s)), and specific examples thereof include the following.

For example, a “C₁₋₆ alkyl group which is optionally substituted with 1to 5 halogen atom(s)” includes, in addition to the “C₁₋₆ alkyl group”, agroup in which the alkyl group is optionally substituted with 1 to 5halogen atom(s). Specifically, in addition to methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, and tert-butyl, for example,trifluoromethyl, trifluoroethyl, tetrafluoroethyl, pentafluoroethyl, andthe like are mentioned.

For example, a “C₁₋₆ alkyl group which is optionally substituted with 1to 5 —OH” includes, in addition to the “C₁₋₆ alkyl group”, a group inwhich the alkyl group is optionally substituted with 1 to 5 hydroxy, andthere are many regioisomers depending on a substitution position.Specifically, in addition to methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl, and tert-butyl, for example, hydroxymethyl,2-hydroxyethyl, 1-hydroxyethyl, 3-hydroxy-1-propyl, 2-hydroxy-1-propyl,1-hydroxy-1-propyl, 2,3-dihydroxy-1-propyl, 1-hydroxy-1-methyl-1-ethyl,2-hydroxy-1-methyl-1-ethyl, 4-hydroxy-1-butyl, 3-hydroxy-1-butyl,2-hydroxy-1-butyl, 1-hydroxy-1-butyl, 3-hydroxy-2-methylpropyl,2-hydroxy-2-methylpropyl, 3-hydroxy-2-hydroxymethylpropyl,2-hydroxy-1,1-dimethyl-1-ethyl, 1-hydroxy-2-methylpropyl,5-hydroxy-1-pentyl, 4-hydroxy-1-pentyl, 3-hydroxy-1-pentyl,2-hydroxy-1-pentyl, 1-hydroxy-1-pentyl, 4-hydroxy-3-methylbutyl,4-hydroxy-2-methylbutyl, 4-hydroxy-1-methylbutyl,3-hydroxy-3-methylbutyl, 3-hydroxy-2-methylbutyl,3-hydroxy-1-methylbutyl, 2-hydroxy-3-methylbutyl,2-hydroxy-2-methylbutyl, 2-hydroxy-1-methylbutyl,3-hydroxy-2,2-dimethylpropyl, 3-hydroxy-1,1-dimethylpropyl,3-hydroxy-2-hydroxymethyl-2-methylpropyl, 6-hydroxy-1-hexyl,4-hydroxy-1,1-dimethyl-1-butyl, 4-hydroxy-3,3-dimethyl-1-butyl,2-hydroxycyclopropyl, 4-hydroxycyclohexyl, and the like are mentioned.

For example, a “C₁₋₆ alkyl group which is optionally substituted with 1to 5 C₁₋₆ alkoxy group(s)” includes, in addition to the “C₁₋₆ alkylgroup”, a group in which the alkyl group is optionally substituted with1 to 5 of the “C₁₋₆ alkoxy groups”.

Specifically, in addition to methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl, and tert-butyl, for example, methoxymethyl,methoxyethyl, methoxypropyl, ethoxyethyl, and the like are mentioned.

For example, a “C₁₋₆ alkyl group which is optionally substituted with 1to 5 C₁₋₆ alkoxy group(s) which is optionally substituted with 1 to 5halogen atom(s)” includes, in addition to the “C₁₋₆ alkyl group” and the“C₁₋₆ alkyl group which is optionally substituted with 1 to 5 C₁₋₆alkoxy group(s)”, a group in which the alkyl group is optionallysubstituted with 1 to 5 of the “C₁₋₆ alkoxy groups” which is optionallysubstituted with 1 to 5 halogen atom(s). Specifically, in addition tomethyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, methoxymethyl, methoxyethyl, and methoxypropyl, for example,trifluoromethoxymethyl, trifluoromethoxyethyl, trifluoromethoxypropyl,and the like are mentioned.

The alkyl group is optionally substituted with 2 to 5 groups optionallyselected from two or more kinds of a halogen atom, —OH, a cyano group, aC₁₋₆ alkoxy group (the C₁₋₆ alkoxy group is optionally substituted with1 to 5 halogen atom(s), 1 to 5 —OH, 1 to 5 C₁₋₆ alkoxy group(s), 1 to 5aryl group(s) (the aryl group is optionally substituted with 1 to 3halogen atom(s)), 1 to 5 heterocyclic group(s) (the heterocyclic groupis optionally substituted with 1 to 3 C₁₋₆ alkyl group(s) or 1 to 3 oxogroup(s)), 1 to 5—S(O)_(i)R^(a) (i is an integer of 0 to 2) group(s), 1to 5 —NR^(b1)R^(c1) group(s), 1 to 5 —SO₂NR^(d)R^(e) group(s), or 1 to 5—CONR^(d)R^(e) group(s)), a —NR^(b1)R^(c1) group, and a heterocyclic oxygroup (the heterocyclic oxy group is optionally substituted with 1 to 3C₁₋₆ alkyl group(s) or 1 to 3 oxo group(s)). For example, a C₁₋₆ alkylgroup which is substituted with one —OH and one C₁₋₆ alkoxy group, suchas 2-hydroxy-3-methoxypropyl and 3-hydroxy-2-methoxypropyl, and the likeare mentioned.

Similarly, the “C₂₋₆ alkenyl group which is optionally substituted with1 to 5 substituent(s) RI” includes, in addition to the “C₂₋₆ alkenylgroup”, a group in which the alkenyl group is optionally substitutedwith 1 to 5 group(s) optionally selected from a halogen atom, —OH, acyano group, a C₁₋₆ alkoxy group (the C₁₋₆ alkoxy group is optionallysubstituted with 1 to 5 halogen atom(s), 1 to 5 —OH, 1 to 5 C₁₋₆ alkoxygroup(s), 1 to 5 aryl group(s) (the aryl group is optionally substitutedwith 1 to 3 halogen atom(s)), 1 to 5 heterocyclic group(s) (theheterocyclic group is optionally substituted with 1 to 3 C₁₋₆ alkylgroup(s) or 1 to 3 oxo group(s)), 1 to 5 —S(O)_(i)R^(a) (i is an integerof 0 to 2) group(s), 1 to 5 —NR^(b1)R^(c1) group(s), 1 to 5—SO₂NR^(d)R^(e) group(s), or 1 to 5 —CONR^(d)R^(e) group(s)), a—NR^(b1)R^(c1) group, and a heterocyclic oxy group (the heterocyclic oxygroup is optionally substituted with 1 to 3 C₁₋₆ alkyl group(s) or 1 to3 oxo group(s)). Specifically, in addition to vinyl, allyl, isopropenyl,2-methylallyl, butenyl, pentenyl, and hexenyl, for example,trifluorovinyl, 2-hydroxyvinyl, 2-methoxyvinyl, 2-trifluoromethoxyvinyl,and the like are mentioned.

The “C₂₋₆ alkynyl group which is optionally substituted with 1 to 5substituent(s) RI” includes, in addition to the “C₂₋₆ alkynyl group”, agroup in which the alkynyl group is optionally substituted with 1 to 5group(s) optionally selected from a halogen atom, —OH, a cyano group, aC₁₋₆ alkoxy group (the C₁₋₆ alkoxy group is optionally substituted with1 to 5 halogen atom(s), 1 to 5 —OH, 1 to 5 C₁₋₆ alkoxy group(s), 1 to 5aryl group(s) (the aryl group is optionally substituted with 1 to 3halogen atom(s)), 1 to 5 heterocyclic group(s) (the heterocyclic groupis optionally substituted with 1 to 3 C₁₋₆ alkyl group(s) or 1 to 3 oxogroup(s)), 1 to 5 —S(O)_(i)R^(a) (i is an integer of 0 to 2) group(s), 1to 5 —NR^(b1)R^(c1) group(s), 1 to 5 —SO₂NR^(d)R^(e) group(s), or 1 to 5—CONR^(d)R^(e) group(s)), a —NR^(b1)R^(c1) group, and a heterocyclic oxygroup (the heterocyclic oxy group is optionally substituted with 1 to 3C₁₋₆ alkyl group(s) or 1 to 3 oxo group(s)). Specifically, in additionto ethynyl, 1-propynyl, 2-propynyl, butynyl, pentynyl, and hexynyl, forexample, fluoroethynyl, 2-hydroxyethynyl, 2-methoxyethynyl,2-trifluoromethoxyethynyl, and the like are mentioned.

The “C₁₋₆ alkoxy group which is optionally substituted with 1 to 5substituent(s) RI” includes, in addition to the “C₁₋₆ alkoxy group”, agroup in which the alkoxy group is optionally substituted with 1 to 5group(s) optionally selected from a halogen atom, —OH, a cyano group, aC₁₋₆ alkoxy group (the C₁₋₆ alkoxy group is optionally substituted with1 to 5 halogen atom(s), 1 to 5 —OH, 1 to 5 C₁₋₆ alkoxy group(s), 1 to 5aryl group(s) (the aryl group is optionally substituted with 1 to 3halogen atom(s)), 1 to 5 heterocyclic group(s) (the heterocyclic groupis optionally substituted with 1 to 3 C₁₋₆ alkyl group(s) or 1 to 3 oxogroup(s)), 1 to 5 —S(O)_(i)R^(a) (i is an integer of 0 to 2) group(s), 1to 5—NR^(b1)R^(c1) group(s), 1 to 5 —SO₂NR^(d)R^(e) group(s), or 1 to 5—CONR^(d)R^(e) group(s)), a —NR^(b1)R^(c1) group, and a heterocyclic oxygroup (the heterocyclic oxy group is optionally substituted with 1 to 3C₁₋₆ alkyl group(s) or 1 to 3 oxo group(s)). Specifically, in additionto methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy,and tert-butoxy, for example, trifluoromethoxy, hydroxymethoxy,2-hydroxyethoxy, 3-hydroxypropoxy, 3-hydroxybutoxy,3-hydroxy-3-methylbutoxy, 2,3-dihydroxypropoxy,3-hydroxy-2-hydroxymethylpropoxy, 3-hydroxy-2-hydroxymethyl-2methylpropoxy, 2-methoxyethoxy, 2-ethoxyethoxy,2-trifluoromethoxyethoxy, 2-methoxy-3-hydroxypropoxy,2-hydroxy-3-methoxypropoxy, and the like are mentioned.

The “aryl group which is optionally substituted with 1 to 5substituent(s) RII” is a group in which any hydrogen atom in the “arylgroup” is optionally substituted with 1 to 5 substituent(s) RII. That isto say, the “aryl group which is optionally substituted with 1 to 5substituent(s) RII” includes, in addition to the “aryl group”, an “arylgroup which is substituted with 1 to 5 group(s) optionally selected froma halogen atom, —OH, a cyano group, a C₁₋₆ alkoxy group (the C₁₋₆ alkoxygroup is optionally substituted with 1 to 5 halogen atom(s), 1 to 5 —OH,1 to 5 C₁₋₆ alkoxy group(s), 1 to 5 aryl group(s) (the aryl group isoptionally substituted with 1 to 3 halogen atom(s)), 1 to 5 heterocyclicgroup(s) (the heterocyclic group is optionally substituted with 1 to 3C₁₋₆ alkyl group(s) or 1 to 3 oxo group(s)), 1 to 5 —S(O)_(i)R^(a) (i isan integer of 0 to 2) group(s), 1 to 5 —SO₂NR^(d)R^(e) group(s), 1 to 5—CONR^(d)R^(e) group(s), or 1 to 5 —NR^(b1)R^(c1) group(s)), a—NR^(b1)R^(c1) group, a heterocyclic oxy group (the heterocyclic oxygroup is optionally substituted with 1 to 3 C₁₋₆ alkyl group(s) or 1 to3 oxo group(s)), a C₁₋₆ alkyl group (the C₁₋₆ alkyl group is optionallysubstituted with 1 to 5 halogen atom(s), 1 to 5 —OH, 1 to 5 C₁₋₆ alkoxygroup(s), 1 to 5 —S(O)_(i)R^(a) (i is an integer of 0 to 2) group(s), 1to 5 —SO₂NR^(d)R^(e) group(s), 1 to 5 —CONR^(d)R^(e) group(s), or 1 to 5—NR^(b1)R^(c1) group(s)), a C₂₋₆ alkenyl group, a C₂₋₇ alkanoyl group,an aralkyloxy group, a heterocyclic group (the heterocyclic group isoptionally substituted with 1 to 3 C₁₋₆ alkyl group(s) or 1 to 3 oxogroup(s)), a heterocyclic carbonyl group (the heterocyclic carbonylgroup is optionally substituted with 1 to 3 C₁₋₆ alkyl group(s) or 1 to3 oxo group(s)), a —S(O)_(i)R^(a) (i is an integer of 0 to 2) group, a—CONR^(d)R^(e) group, and a —CONR^(d)R^(e1) group”.

Specifically, in addition to the “aryl group”, for example, an “arylgroup which is optionally substituted with 1 to 5 halogen atom(s)”, an“aryl group which is substituted with 1 to 5 group(s) optionallyselected from the “C₁₋₆ alkoxy group” (the C₁₋₆ alkoxy group isoptionally substituted with 1 to 5 halogen atom(s), 1 to 5 —OH, 1 to 5C₁₋₆ alkoxy group(s), 1 to 5 aryl group(s) (the aryl group is optionallysubstituted with 1 to 3 halogen atom(s)), 1 to 5 heterocyclic group(s)(the heterocyclic group is optionally substituted with 1 to 3 C₁₋₆ alkylgroup(s) or 1 to 3 oxo group(s)), 1 to 5 —S(O)_(i)R^(a) (i is an integerof 0 to 2) group(s), 1 to 5 —SO₂NR^(d)R^(e) group(s), 1 to 5—CONR^(d)R^(e) group(s), or 1 to 5 —NR^(b1)R^(c1) group(s))”, an “arylgroup which is substituted with 1 to 5 group(s) optionally selected fromthe “C₁₋₆ alkyl group” (the C₁₋₆ alkyl group is optionally substitutedwith 1 to 5 halogen atom(s), 1 to 5 —OH, 1 to 5 C₁₋₆ alkoxy group(s), 1to 5—S(O)_(i)R^(a) (i is an integer of 0 to 2) group(s), 1 to 5—SO₂NR^(d)R^(e) group(s), 1 to 5 —CONR^(d)R^(e) group(s), or 1 to 5—NR^(b1)R^(c1) group(s))”, and the like are mentioned.

The aryl group is optionally substituted with 2 to 5 groups optionallyselected from two or more kinds of a halogen atom, —OH, a cyano group, aC₁₋₆ alkoxy group (the C₁₋₆ alkoxy group is optionally substituted with1 to 5 halogen atom(s), 1 to 5 —OH, 1 to 5 C₁₋₆ alkoxy group(s), 1 to 5aryl group(s) (the aryl group is optionally substituted with 1 to 3halogen atom(s)), 1 to 5 heterocyclic group(s) (the heterocyclic groupis optionally substituted with 1 to 3 C₁₋₆ alkyl group(s) or 1 to 3 oxogroup(s)), 1 to 5 —S(O)_(i)R^(a) (i is an integer of 0 to 2) group(s), 1to 5 —SO₂NR^(d)R^(e) group(s), 1 to 5 —CONR^(d)R^(e) group(s), or 1 to 5—NR^(b1)R^(c1) group(s)), a —NR^(b1)R^(c1) group, a heterocyclic oxygroup (the heterocyclic oxy group is optionally substituted with 1 to 3C₁₋₆ alkyl group(s) or 1 to 3 oxo group(s)), a C₁₋₆ alkyl group (theC₁₋₆ alkyl group is optionally substituted with 1 to 5 halogen atom(s),1 to 5 —OH, 1 to 5 C₁₋₆ alkoxy group(s), 1 to 5 —S(O)_(i)R^(a) (i is aninteger of 0 to 2) group(s), 1 to 5 —SO₂NR^(d)R^(e) group(s), 1 to 5—CONR^(d)R^(e) group(s), or 1 to 5 —NR^(b1)R^(c1) group(s)), a C₂₋₆alkenyl group, a C₂₋₇ alkanoyl group, an aralkyloxy group, aheterocyclic group (the heterocyclic group is optionally substitutedwith 1 to 3 C₁₋₆ alkyl group(s) or 1 to 3 oxo group(s)), a heterocycliccarbonyl group (the heterocyclic carbonyl group is optionallysubstituted with 1 to 3 C₁₋₆ alkyl group(s) or 1 to 3 oxo group(s)), a—S(O)_(i)R^(a) (i is an integer of 0 to 2) group, a —CONR^(d)R^(e)group, and a —CONR^(d)R^(e1) group. Specifically, for example, an “arylgroup which is optionally substituted with 1 or 2 of the “C₁₋₆ alkylgroups” and 1 or 2 of the “C₁₋₆ alkoxy groups” (the C₁₋₆ alkoxy group isoptionally substituted with 1 to 5 halogen atom(s), 1 to 5 —OH, 1 to 5C₁₋₆ alkoxy group(s), 1 to 5 aryl group(s) (the aryl group is optionallysubstituted with 1 to 3 halogen atom(s)), 1 to 5 heterocyclic group(s)(the heterocyclic group is optionally substituted with 1 to 3 C₁₋₆ alkylgroup(s) or 1 to 3 oxo group(s)), 1 to 5—S(O)_(i)R^(a) (i is an integerof 0 to 2) group(s), 1 to 5 —SO₂NR^(d)R^(e) group(s), 1 to 5—CONR^(d)R^(e) group(s), or 1 to 5 —NR^(b1)R^(c1) group(s))” and thelike are mentioned. More preferably, for example, an “aryl group whichis optionally substituted with 1 or 2 of the “C₁₋₆ alkyl groups” and oneof the “C₁₋₆ alkoxy group” (the C₁₋₆ alkoxy group is optionallysubstituted with 1 or 2 —OH, 1 or 2 C₁₋₆ alkoxy group(s), 1 or 2non-aromatic heterocyclic group(s) (the heterocyclic group is optionallysubstituted with a C₁₋₆ alkyl group), 1 or 2—S(O)_(i)R^(a) (i is aninteger of 0 to 2) group(s), or 1 or 2 —NR^(b1)R^(c1) group(s))”, andthe like are mentioned.

Examples of the “aryl group which is optionally substituted with 1 to 5substituent(s) RII” more specifically include, in addition to phenyl,(1- or 2-)naphthyl, indanyl, and tetrahydronaphthyl, (2-, 3-, or4-)fluorophenyl, (2-, 3-, or 4-)chlorophenyl, (2,6-, 2,5-, 2,4-, 2,3-,or 3,5-)difluorophenyl, 4-chloro-2-fluorophenyl, (2-, 3-, or4-)hydroxyphenyl, (2-, 3-, or 4-)cyanophenyl, (2,6-, 2,5-, 2,4-, 2,3-,3,4-, or 3,5-)dicyanophenyl, (2-, 3-, or 4-)methoxyphenyl, (2-, 3-, or4-)ethoxyphenyl, (2-, 3-, or 4-)propoxyphenyl, (2-, 3-, or4-)isopropoxyphenyl, (2-, 3-, or 4-)trifluoromethoxyphenyl, (2-, 3-, or4-)methylphenyl, (2-, 3-, or 4-)ethylphenyl, (2-, 3-, or4-)propylphenyl, (2-, 3-, or 4-)isopropylphenyl, (2-, 3-, or4-)isobutylphenyl, (2-, 3-, or 4-)tert-butylphenyl, (2-, 3-, or4-)trifluoromethylphenyl, (2,6-, 2,5-, 2,4-, 2,3-, or3,5-)dimethoxyphenyl, (2,6-, 2,5-, 2,4-, or 2,3-) dimethylphenyl,3,5-ditrifluoromethylphenyl, (4- or 5-)fluoro-(2- or 3-)methylphenyl,3-fluoro-4-methylphenyl, 2-chloro-(4- or 5-)methylphenyl, (4- or5-)fluoro-2-trifluoromethylphenyl, (4- or5-)chloro-2-trifluoromethylphenyl, 2-(fluoro- orchloro-)₅-trifluoromethylphenyl, (4- or 5-)fluoro-(2- or3-)methoxyphenyl, 2-fluoro-(3-, 4-, or 5-)methoxyphenyl, (4- or5-)chloro-(2- or 3-)methoxyphenyl, 2-chloro-(3-, 4-, or5-)methoxyphenyl, (4- or 5-)fluoro-2-ethoxyphenyl, (4- or5-)chloro-2-ethoxyphenyl, 3-(fluoro- or chloro-)4-ethoxyphenyl,2-methoxy-5-methylphenyl, 4-methoxy-2-methylphenyl, 4-methoxy-(2,6-,2,5-, or 2,3-)dimethylphenyl, (2-, 3-, or 4-)hydroxymethylphenyl,4-cyano-3-hydroxymethylphenyl, (3- or 4-)(2-hydroxyethyl)phenyl, (3- or4-)(3-hydroxy-3-methylbutoxy)phenyl, 4-(2-hydroxyethoxy)-2-methylphenyl,4-(2,3-dihydroxypropoxy)-2-methylphenyl,4-(3-hydroxy-3-methylbutoxy)-2-methylphenyl,3-(3-hydroxy-3-methylbutoxy)-2-methylphenyl, 4-(2-hydroxyethoxy)-(2,6-,2,5-, or 2,3-)dimethylphenyl, 4-(3-hydroxypropoxy)-2-methylphenyl,4-(3-hydroxypropoxy)-(2,6-, 2,5-, or 2,3-)dimethylphenyl,4-(2,3-dihydroxypropoxy)-(2,6-, 2,5-, or 2,3-)dimethylphenyl,4-((2R)-2,3-dihydroxypropoxy)-(2,6-, 2,5-, or 2,3-)dimethylphenyl,4-((2S)-2,3-dihydroxypropoxy)-(2,6-, 2,5-, or 2,3-)dimethylphenyl,4-(3-hydroxy-2-hydroxymethylpropoxy)-2-methylphenyl,4-(3-hydroxy-2-hydroxymethyl-2-methylpropoxy)-2-methylphenyl,4-(3-hydroxybutoxy)-2-methylphenyl,4-((3S)-3-hydroxybutoxy)-2-methylphenyl,4-((3R)-3-hydroxybutoxy)-2-methylphenyl,4-(3-hydroxy-2-hydroxymethylpropoxy)-(2,6-, 2,5-, or2,3-)dimethylphenyl,4-(3-hydroxy-2-hydroxymethyl-2-methylpropoxy)-(2,6-, 2,5-, or2,3-)dimethylphenyl, 4-(3-hydroxybutoxy)-(2,6-, 2,5-, or2,3-)dimethylphenyl, 4-((3S)-3-hydroxybutoxy)-(2,6-, 2,5-, or2,3-)dimethylphenyl, 4-((3R)-3-hydroxybutoxy)-(2,6-, 2,5-, or2,3-)dimethylphenyl, 4-(3-hydroxy-3-methylbutoxy)-(2,6-, 2,5-, or2,3-)dimethylphenyl, 4-(3-aminopropoxy)-2-methylphenyl,4-(3-aminopropoxy)-(2,6-, 2,5-, or 2,3-)dimethylphenyl,4-(2-(2-oxo-1-pyrrolidinyl)ethoxy)-2-methylphenyl,4-(2-(2-oxo-1-pyrrolidinyl)ethoxy)-(2,6-, 2,5-, or 2,3-)dimethylphenyl,4-(3-(2-oxo-1-pyrrolidinyl)propoxy)-2-methylphenyl,4-(3-(2-oxo-1-pyrrolidinyl)propoxy)-(2,6-, 2,5-, or 2,3-)dimethylphenyl,4-(5-oxo-2-pyrrolidinyl)methoxy-2-methylphenyl,4-(5-oxo-2-pyrrolidinyl)methoxy-(2,6-, 2,5-, or 2,3-)dimethylphenyl,4-(2-ethoxy-ethoxy)-2-methylphenyl, 4-(2-ethoxy-ethoxy)-(2,6-, 2,5-, or2,3-)dimethylphenyl, 4-(2-methylsulfonyl-ethoxy)-2-methylphenyl,4-(2-methylsulfonyl-ethoxy)-(2,6-, 2,5-, or 2,3-)dimethylphenyl,4-(3-methylsulfonyl-propoxy)phenyl,4-(3-methylsulfonyl-propoxy)-2-methylphenyl,4-(3-methylsulfonyl-propoxy)-(2,6-, 2,5-, or 2,3-)dimethylphenyl,4-((1,1-dioxidetetrahydro-2H-thiopyran-4-yl)oxy)-2-methylphenyl,4((1,1-dioxidetetrahydro-2H-thiopyran-4-yl)oxy)-(2,6-, 2,5-, or2,3-)dimethylphenyl,4-((4-hydroxy-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)methoxy)-2-methylphenyl,

4-((4-hydroxy-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)methoxy)-(2,6-,2,5-, or 2,3-)dimethylphenyl,4-((3-methyloxetan-3-yl)methoxy)-2-methylphenyl,4-((3-methyloxetan-3-yl)methoxy)-(2,6-, 2,5-, or 2,3-)dimethylphenyl,4-(2-acetylamino-ethoxy)-2-methylphenyl, 4-(2-acetylamino-ethoxy)-(2,6-,2,5-, or 2,3-)dimethylphenyl, 4-(3-acetylamino-propoxy)-2-methylphenyl,4-(3-acetylamino-propoxy)-(2,6-, 2,5-, or 2,3-)dimethylphenyl,4-(2-methylsulfonylamino-ethoxy)-2-methylphenyl,4-(2-methylsulfonylamino-ethoxy)-(2,6-, 2,5-, or 2,3-)dimethylphenyl,4-(3-methylsulfonylamino-propoxy)-2-methylphenyl,4-(3-methylsulfonylamino-propoxy)-(2,6-, 2,5-, or 2,3-)dimethylphenyl,4-(2-carbamoyl-ethoxy)-2-methylphenyl, 4-(2-carbamoyl-ethoxy)-(2,6-,2,5-, or 2,3-)dimethylphenyl, 4-(3-carbamoyl-propoxy)-2-methylphenyl,4-(3-carbamoyl-propoxy)-(2,6-, 2,5-, or 2,3-)dimethylphenyl,4-(2-methylcarbamoyl-ethoxy)-2-methylphenyl,4-(2-methylcarbamoyl-ethoxy)-(2,6-, 2,5-, or 2,3-)dimethylphenyl,4-(3-methylcarbamoyl-propoxy)-2-methylphenyl,4-(3-methylcarbamoyl-propoxy)-(2,6-, 2,5-, or 2,3-)dimethylphenyl,4-(2-dimethylcarbamoyl-ethoxy)-2-methylphenyl,4-(2-dimethylcarbamoyl-ethoxy)-(2,6-, 2,5-, or 2,3-)dimethylphenyl,4-(3-dimethylcarbamoyl-propoxy)-2-methylphenyl,4-(3-dimethylcarbamoyl-propoxy)-(2,6-, 2,5-, or 2,3-)dimethylphenyl,4-(2-sulfamoyl-ethoxy)-2-methylphenyl, 4-(2-sulfamoyl-ethoxy)-(2,6-,2,5-, or 2,3-)dimethylphenyl, 4-(3-sulfamoyl-propoxy)-2-methylphenyl,4-(3-sulfamoyl-propoxy)-(2,6-, 2,5-, or 2,3-)dimethylphenyl,4-(2-methylsulfamoyl-ethoxy)-2-methylphenyl,4-(2-methylsulfamoyl-ethoxy)-(2,6-, 2,5-, or 2,3-)dimethylphenyl,4-(3-methylsulfamoyl-propoxy)-2-methylphenyl,4-(3-methylsulfamoyl-propoxy)-(2,6-, 2,5-, or 2,3-)dimethylphenyl,4-(2-dimethylsulfamoyl-ethoxy)-2-methylphenyl,4-(2-dimethylsulfamoyl-ethoxy)-(2,6-, 2,5-, or 2,3-)dimethylphenyl,4-(3-dimethylsulfamoyl-propoxy)-2-methylphenyl,4-(3-dimethylsulfamoyl-propoxy)-(2,6-, 2,5-, or 2,3-)dimethylphenyl,

3-fluoro-4-(3-hydroxy-3-methylbutoxy)-2-methylphenyl,3-fluoro-4-(3-hydroxy-3-methylbutoxy)-(2,6- or 2,5-)dimethylphenyl,3-fluoro-4-(3-methylsulfonyl-propoxy)-2-methylphenyl,3-fluoro-4-(3-methylsulfonyl-propoxy)-(2,6- or 2,5-)dimethylphenyl,

4-(3-hydroxy-3-methylbutoxy)-2-hydroxymethylphenyl,4-(3-hydroxy-3-methylbutoxy)-6-methyl-2-hydroxymethylphenyl,

4-(3-methylsulfonyl-propoxy)-2-hydroxymethylphenyl,4-(3-methylsulfonyl-propoxy)-6-methyl-2-hydroxymethylphenyl, (2-, 3-, or4-)vinylphenyl, (2-, 3-, or 4-)acetylphenyl, (2-, 3-, or4-)benzyloxyphenyl, 2-benzyloxy-(3-, 4-, 5-, or 6-)fluorophenyl,4-benzyloxy-(2- or 3-)fluorophenyl, 4-benzyloxy-(2- or 3-)methylphenyl,(2-, 3-, or 4-)methylsulfonylphenyl, (2-, 3-, or 4-)carbamoylphenyl,(2-, 3-, or 4-)N-methylcarbamoylphenyl, (2-, 3-, or4-)N,N-dimethylcarbamoylphenyl, (2-, 3-, or4-)(N-(2-hydroxyethyl)carbamoyl)phenyl, (2-, 3-, or4-)(N-(2-methoxyethyl)carbamoyl)phenyl, (2-, 3-, or4-)(N-(2-hydroxyethyl)-N-methylcarbamoyl)phenyl, (2-, 3-, or4-)(N-(2-methoxyethyl)-N-methylcarbamoyl)phenyl, (2-, 3-, or4-)(N-(2-methylsulfonyl-ethyl)carbamoyl)phenyl, (2-, 3-, or4-)(N-(2-methylsulfonyl-ethyl)-N-methylcarbamoyl)phenyl,4-cyano-3-carbamoylphenyl, 3-cyano-4-carbamoylphenyl, (2-, 3-, or4-)(pyrrolidine-1-yl)carbonylphenyl, (2-, 3-, or 4-)morpholinophenyl,4-cyano-3-morpholinophenyl, (2-, 3-, or 4-)(2-oxooxazolidin-3-yl)phenyl,4-cyano-3-(2-oxooxazolidin-3-yl)phenyl, (4-, 5-, 6-, or7-)fluoro-1-indanyl, (4-, 5-, 6-, or 7-)chloro-1-indanyl, (4-, 5-, 6-,or 7-)bromo-1-indanyl, (4-, 5-, 6-, or 7-)trifluoromethyl-1-indanyl,(4-, 5-, 6-, or 7-)fluoro-2-indanyl, (4-, 5-, 6-, or7-)chloro-2-indanyl, (4-, 5-, 6-, or 7-)bromo-2-indanyl, (4-, 5-, 6-, or7-)trifluoromethyl-2-indanyl, (2-, 3-, 4-, 5-, 6-, 7-, or8-)fluoro-naphthalene-1-yl, (2-, 3-, 4-, 5-, 6-, 7-, or8-)chloro-naphthalene-1-yl, and (2-, 3-, 4-, 5-, 6-, 7-, or8-)methyl-naphthalene-1-yl.

The “heterocyclic group which is optionally substituted with 1 to 5substituent(s) RII” is a group in which any hydrogen atom in the“heterocyclic group” is optionally substituted with 1 to 5substituent(s) RII. Namely, the “heterocyclic group which is optionallysubstituted with 1 to 5 substituent(s) RII” is, in addition to theunsubstituted “heteroaryl group” and the “non-aromatic heterocyclicgroup” both exemplified above as a “heterocyclic group” (these rings areeach a monovalent group obtained by removing any hydrogen atom from aring having a monocyclic ring or a fused ring that is a 3- to14-membered ring, or preferably a 3- to 12-membered ring, containing, inaddition to carbon atoms, at least one hetero atom (preferably 1 to 4atom(s)) optionally selected from N, O, and S): a “heterocyclic groupwhich is substituted with 1 to 5 group(s) optionally selected from ahalogen atom, —OH, a cyano group, a C₁₋₆ alkoxy group (the C₁₋₆ alkoxygroup is optionally substituted with 1 to 5 halogen atom(s), 1 to 5 —OH,1 to 5 C₁₋₆ alkoxy group(s), 1 to 5 aryl group(s) (the aryl group isoptionally substituted with 1 to 3 halogen atom(s)), 1 to 5 heterocyclicgroup(s) (the heterocyclic group is optionally substituted with 1 to 3C₁₋₆ alkyl group(s) or 1 to 3 oxo group(s)), 1 to 5 —S(O)_(i)R^(a) (i isan integer of 0 to 2) group(s), 1 to 5 —SO₂NR^(d)R^(e) group(s), 1 to 5—CONR^(d)R^(e) group(s), or 1 to 5 —NR^(b1)R^(c1) group(s)), a—NR^(b1)R^(c1) group, a heterocyclic oxy group (the heterocyclic oxygroup is optionally substituted with 1 to 3 C₁₋₆ alkyl group(s) or 1 to3 oxo group(s)), a C₁₋₆ alkyl group (the C₁₋₆ alkyl group is optionallysubstituted with 1 to 5 halogen atom(s), 1 to 5 —OH, 1 to 5 C₁₋₆ alkoxygroup(s), 1 to 5 —S(O)_(i)R^(a) (i is an integer of 0 to 2) group(s), 1to 5 —SO₂NR^(d)R^(e) group(s), 1 to 5 —CONR^(d)R^(e) group(s), or 1 to 5—NR^(b1)R^(c1) group(s)), a C₂₋₆ alkenyl group, a C₂₋₇ alkanoyl group,an aralkyloxy group, a heterocyclic group (the heterocyclic group isoptionally substituted with 1 to 3 C₁₋₆ alkyl group(s) or 1 to 3 oxogroup(s)), a heterocyclic carbonyl group (the heterocyclic carbonylgroup is optionally substituted with 1 to 3 C₁₋₆ alkyl group(s) or 1 to3 oxo group(s)), a —S(O)_(i)R^(a) (i is an integer of 0 to 2) group, a—CONR^(d)R^(e) group, and a —CONR^(d)R^(e1) group”.

Specific examples of the “heterocyclic group which is optionallysubstituted with 1 to 5 substituent(s) RII” include, in addition to the“heterocyclic group”, a “heterocyclic group optionally substituted with1 to 5 halogen atom(s)”, a “heterocyclic group substituted with 1 to 5group(s) optionally selected from the “C₁₋₆ alkoxy group” (the C₁₋₆alkoxy group is optionally substituted with 1 to 5 halogen atom(s), 1 to5 —OH, 1 to 5 C₁₋₆ alkoxy group(s), 1 to 5 aryl group(s) (the aryl groupis optionally substituted with 1 to 3 halogen atom(s)), 1 to 5heterocyclic group(s) (the heterocyclic group is optionally substitutedwith 1 to 3 C₁₋₆ alkyl group(s) or 1 to 3 oxo group(s)), 1 to 5—S(O)_(i)R^(a) (i is an integer of 0 to 2) group(s), 1 to 5—SO₂NR^(d)R^(e) group(s), 1 to 5 —CONR^(d)R^(e) group(s), or 1 to 5—NR^(b1)R^(c1) group(s))”, and a “heterocyclic group substituted with 1to 5 group(s) optionally selected from the “C₁₋₆ alkyl group” (the C₁₋₆alkyl group is optionally substituted with 1 to 5 halogen atom(s), 1 to5 —OH, 1 to 5 C₁₋₆ alkoxy group(s), 1 to 5—S(O)_(i)R^(a) (i is aninteger of 0 to 2) group(s), 1 to 5 —SO₂NR^(d)R^(e) group(s), 1 to 5—CONR^(d)R^(e) group(s), or 1 to 5 —NR^(b1)R^(c1) group(s))”. Morespecific examples thereof include a “heteroaryl group substituted with 1to 5 group(s) optionally selected from the “C₁₋₆ alkyl group” (the C₁₋₆alkyl group is optionally substituted with 1 to 5 halogen atom(s), 1 to5—OH, 1 to 5 C₁₋₆ alkoxy group(s), 1 to 5 —S(O)_(i)R^(a) (i is aninteger of 0 to 2) group(s), 1 to 5 —SO₂NR^(d)R^(e) group(s), 1 to 5—CONR^(d)R^(e) group(s), or 1 to 5 —NR^(b1)R^(c1) group(s))” and a“heteroaryl group substituted with 1 to 5 groups(s) optionally selectedfrom the “C₁₋₆ alkoxy group” (the C₁₋₆ alkoxy group is optionallysubstituted with 1 to 5 halogen atom(s), 1 to 5 —OH, 1 to 5 C₁₋₆ alkoxygroup(s), 1 to 5 aryl group(s) (the aryl group is optionally substitutedwith 1 to 3 halogen atom(s)), 1 to 5 heterocyclic group(s) (theheterocyclic group is optionally substituted with 1 to 3 C₁₋₆ alkylgroup(s) or 1 to 3 oxo group(s)), 1 to 5 —S(O)_(i)R^(a) (i is an integerof 0 to 2) group(s), 1 to 5 —SO₂NR^(d)R^(e) group(s), 1 to5—CONR^(d)R^(e) group(s), or 1 to 5 —NR^(b1)R^(c1) group(s))”.

Furthermore, the heterocyclic group is optionally substituted with 2 to5 groups optionally selected from 2 or more kinds of a halogen atom,—OH, a cyano group, a C₁₋₆ alkoxy group (the C₁₋₆ alkoxy group isoptionally substituted with 1 to 5 halogen atom(s), 1 to 5 —OH, 1 to 5C₁₋₆ alkoxy group(s), 1 to 5 aryl group(s) (the aryl group is optionallysubstituted with 1 to 3 halogen atom(s)), 1 to 5 heterocyclic group(s)(the heterocyclic group is optionally substituted with 1 to 3 C₁₋₆ alkylgroup(s) or 1 to 3 oxo group(s)), 1 to 5 —S(O)_(i)R^(a) (i is an integerof 0 to 2) group(s), 1 to 5 —SO₂NR^(d)R^(e) group(s), 1 to 5—CONR^(d)R^(e) group(s), or 1 to 5 —NR^(b1)R^(c1) group(s)), a—NR^(b1)R^(c1) group, a heterocyclic oxy group (the heterocyclic oxygroup is optionally substituted with 1 to 3 C₁₋₆ alkyl group(s) or 1 to3 oxo group(s)), a C₁₋₆ alkyl group (the C₁₋₆ alkyl group is optionallysubstituted with 1 to 5 halogen atom(s), 1 to 5 —OH, 1 to 5 C₁₋₆ alkoxygroup(s), 1 to 5—S(O)_(i)R^(a) (i is an integer of 0 to 2) group(s), 1to 5 —SO₂NR^(d)R^(e) group(s), 1 to 5 —CONR^(d)R^(e) group(s), or 1 to 5—NR^(b1)R^(c1) group(s)), a C₂₋₆ alkenyl group, a C₂₋₇ alkanoyl group,an aralkyloxy group, a heterocyclic group (the heterocyclic group isoptionally substituted with 1 to 3 C₁₋₆ alkyl group(s) or 1 to 3 oxogroup(s)), a heterocyclic carbonyl group (the heterocyclic carbonylgroup is optionally substituted with 1 to 3 C₁₋₆ alkyl group(s) or 1 to3 oxo group(s)), a —S(O)_(i)R^(a) (i is an integer of 0 to 2) group, a—CONR^(d)R^(e) group, and a —CONR^(d)R^(e1) group. Specific examplesthereof include a “heterocyclic group optionally substituted with 1 or 2“C₁₋₆ alkyl group(s)” and 1 or 2 “C₁₋₆ alkoxy group(s)” (the C₁₋₆ alkoxygroup is optionally substituted with 1 to 5 halogen atom(s), 1 to 5 —OH,1 to 5 C₁₋₆ alkoxy group(s), 1 to 5 aryl group(s) (the aryl group isoptionally substituted with 1 to 3 halogen atom(s)), 1 to 5 heterocyclicgroup(s) (the heterocyclic group is optionally substituted with 1 to 3C₁₋₆ alkyl group(s) or 1 to 3 oxo group(s)), 1 to 5 —S(O)_(i)R^(a) (i isan integer of 0 to 2) group(s), 1 to 5 —SO₂NR^(d)R^(e) group(s), 1 to 5—CONR^(d)R^(e) group(s), or 1 to 5 —NR^(b1)R^(c1) group(s))”. Morepreferred examples thereof include a “heteroaryl group optionallysubstituted with 1 or 2 “C₁₋₆ alkyl group(s)” and one “C₁₋₆ alkoxygroup” (the C₁₋₆ alkoxy group is optionally substituted with 1 or 2 —OH,1 or 2 C₁₋₆ alkoxy group(s), 1 or 2 non-aromatic heterocyclic group(s)(the heterocyclic group is optionally substituted with a C₁₋₆ alkylgroup), 1 or 2—S(O)_(i)R^(a) (i is an integer of 0 to 2) group(s), or 1or 2 —NR^(b1)R^(c1) group(s))”.

The “heteroaryl group” in the “heterocyclic group which is optionallysubstituted with 1 to 5 substituent(s) RII” may be monocyclic orring-fused. The monocyclic heteroaryl group preferably has a 5- to7-membered ring, and examples thereof include those groups described inthe definition of the “heteroaryl group”, such as pyrrolyl, furyl,thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl,isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, furazanyl, 1,2,3-thiadiazolyl,1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, tetrazolyl, pyridyl,pyridazinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl,1,3,5-triazinyl, 2H-1,2,3-thiadiazinyl, 4H-1,2,4-thiadiazinyl,6H-1,3,4-thiadiazinyl, 1,4-diazepinyl, and 1,4-oxazepinyl. Thering-fused heteroaryl group preferably has an 8- to 14-membered ring,and examples thereof include a monovalent group obtained by removing anyhydrogen atom from a fused ring formed by fusing the 5- to 7-memberedheterocyclic ring and a monocyclic aryl group (such as a benzene ring)or a monocyclic heteroaryl group. The hydrogen atom is optionallyremoved from any of the fused rings. Specific examples include thosegroups described in the definition of the “heteroaryl group”, such asindolyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothienyl,isobenzothienyl, benzoxazolyl, 1,2-benzisoxazolyl, benzothiazolyl,1,2-benzisothiazolyl, 1H-benzimidazolyl, 1H-indazolyl,1H-benzotriazolyl, 2,1,3-benzothiadiazinyl, chromenyl, isochromenyl,4H-1,4-benzoxazinyl, 4H-1,4-benzothiazinyl, quinolyl, isoquinolyl,cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, benzoxazepinyl,benzoazepinyl, benzodiazepinyl, naphthyridinyl, purinyl, pteridinyl,carbazolyl, carbolinyl, acridinyl, phenoxazinyl, phenothiazinyl,phenazinyl, phenoxathiinyl, thianthrenyl, phenanthridinyl,phenanthrolinyl, indolizinyl, thieno[3,2-c]pyridyl,thiazolo[5,4-c]pyridyl, pyrrolo[1,2-b]pyridazinyl,pyrazolo[1,5-a]pyridyl, imidazo[1,2-a]pyridyl, imidazo[1,5-a]pyridyl,imidazo[1,2-b]pyridazinyl, imidazo[1,5-a]pyrimidinyl,1,2,4-triazolo[4,3-a]pyridyl, 1,2,4-triazolo[4,3-b]pyridazinyl,1H-pyrazolo[3,4-b]pyridyl, 1,2,4-triazolo[1,5-a]pyrimidinyl, anddibenzofuranyl. Specific examples thereof also include a ring-fusedheteroaryl group which is partly hydrogenated, such as indolinyl,dihydrobenzofuranyl, dihydroisobenzofuranyl, dihydrobenzoxazolyl,dihydrobenzothiazolyl, chromanyl, isochromanyl,3,4-dihydro-2H-1,4-benzoxazinyl, 3,4-dihydro-2H-1,4-benzothiazinyl,tetrahydroquinolyl, tetrahydroisoquinolyl, tetrahydroquinoxalinyl,1,4-benzodioxanyl, 1,3-benzodioxolyl, tetrahydrobenzoxazepinyl,tetrahydrobenzoazepinyl, and 6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridyl.The ring-fused heteroaryl group which is partly hydrogenated preferablyhas an 8- to 12-membered ring, namely a monovalent group obtained byremoving any hydrogen atom from a fused ring which is partlyhydrogenated and formed by fusing the 5- to 7-membered heterocyclic ringand a monocyclic aryl group (such as a benzene ring) or a monocyclicheteroaryl group. Any of the hydrogen atom in the aryl group or in theheterocyclic moiety and of the hydrogen atom in the hydrogenated moietyis optionally removed. In the case of tetrahydroquinolyl, examples ofthe partly hydrogenated ring-fused heteroaryl group include5,6,7,8-tetrahydroquinolyl and 1,2,3,4-tetrahydroquinolyl. Depending onthe position in these groups from which any hydrogen atom is removed,-2-yl, -3-yl, -4-yl, -5-yl, -6-yl, -7-yl, and -8-yl are exemplified inthe case of 5,6,7,8-tetrahydroquinolyl, and in the case of1,2,3,4-tetrahydroquinolyl, -1-yl, -2-yl, -3-yl, -4-yl, -5-yl, -6-yl,-7-yl, and -8-yl are exemplified.

Examples of the “non-aromatic heterocyclic group” in the “heterocyclicgroup which is optionally substituted with 1 to 5 substituent(s) RII”include a 3- to 8-membered saturated or unsaturated non-aromaticheterocyclic group. Specific examples thereof include aziridinyl,azetidinyl, oxiranyl, oxetanyl, thietanyl, pyrrolidinyl,tetrahydrofuryl, thiolanyl, pyrazolinyl, pyrazolidinyl, piperidinyl,dihydropyranyl, tetrahydropyranyl (oxanyl), tetrahydrothiopyranyl,piperazinyl, dioxanyl, oxazolinyl, isoxazolinyl, oxazolidinyl,isoxazolidinyl, thiazolinyl, isothiazolinyl, thiazolidinyl,isothiazolidinyl, oxadiazolinyl, oxadiazolidinyl, morpholinyl,thiomorpholinyl, quinuclidinyl, and oxepanyl. The “non-aromaticheterocyclic group” means a monovalent group obtained by removing anyhydrogen atom from the ring.

Specific examples of the “heterocyclic group which is optionallysubstituted with 1 to 5 substituent(s) RII” include pyrrolyl, furyl,thienyl, pyrazolyl, isoxazolyl, pyridyl, pyrimidinyl, indolyl,1H-benzimidazolyl, quinolyl, dibenzofuranyl, dihydrobenzofuranyl,dihydroisobenzofuranyl, chromanyl, 1,3-benzodioxanyl, 1,4-benzodioxanyl,piperidinyl, dihydropyranyl, and tetrahydropyranyl (oxanyl). Furtherspecific examples thereof include 2-pyrrolyl, 3-pyrrolyl, 2-furyl,3-furyl, 2-thienyl, 3-thienyl, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl,5-pyrazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-pyridyl,3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl,1-indolyl, 2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl,7-indolyl, 1H-benzimidazol-1-yl, 1H-benzimidazol-2-yl,1H-benzimidazol-4-yl, 1H-benzimidazol-5-yl, 1H-benzimidazol-6-yl,1H-benzimidazol-7-yl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl,6-quinolyl, 7-quinolyl, 8-quinolyl, 1-dibenzofuranyl, 2-dibenzofuranyl,3-dibenzofuranyl, 4-dibenzofuranyl, 1,4-benzodioxazine-2-yl,1,4-benzodioxazine-3-yl, 1,4-benzodioxazine-5-yl,1,4-benzodioxazine-6-yl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl,piperidin-4-yl, 3,6-dihydro-2H-pyran-4-yl, and 4-tetrahydropyranyl(4-oxanyl). Any hydrogen atom of the groups is optionally substitutedwith 1 to 5 substituent(s) RII. Specific examples thereof include (3-,4-, or 5-)chlorothiophen-2-yl, (2-, 4-, or 5-)chlorothiophen-3-yl, (3-,4-, or 5-)acetylthiophen-2-yl, 1-methylpyrazol-4-yl,3,5-dimethylisoxazol-4-yl, (2-, 4-, 5-, or 6-)fluoropyridin-3-yl, (2-,4-, 5-, or 6-)chloropyridin-3-yl, (2-, 4-, 5-, or6-)hydroxypyridin-3-yl, (3-, 4-, 5-, or 6-)cyanopyridin-2-yl, (2-, 4-,5-, or 6-)cyanopyridin-3-yl, (2- or 3-)cyanopyridin-4-yl, (3-, 4-, 5-,or 6-)methoxypyridin-2-yl, (2-, 4-, 5-, or 6-)methoxypyridin-3-yl, (2-or 3-)methoxypyridin-4-yl, (2-, 4-, 5-, or 6-)ethoxypyridin-3-yl, (2-,4-, 5-, or 6-)cyclopropylmethoxypyridin-3-yl, (3-, 4-, 5-, or6-)methylpyridin-2-yl, (2-, 4-, 5-, or 6-)methylpyridin-3-yl, (2- or3-)methylpyridin-4-yl, (2-, 4-, 5-, or 6-)trifluoromethylpyridin-3-yl,6-(3-hydroxybutoxy)pyridin-3-yl,6-(3-hydroxy-3-methylbutoxy)pyridin-3-yl,6-(2-ethoxyethoxy)pyridin-3-yl,6-(3-methylsulfonyl-propoxy)pyridin-3-yl, (2,4-, 2,5-, 2,6-, 4,5-, 4,6-,or 5,6-)dimethylpyridin-3-yl, (2,4-, 2,5-, 2,6-, 4,5-, 4,6-, or5,6-)dimethoxypyridin-3-yl, 6-isopropyl-(2-, 4-, or5-)chloropyridin-3-yl, 6-methoxy-(2-, 4-, or 5-)methylpyridin-3-yl,6-(2-hydroxyethoxy)-(2- or 4-)methylpyridin-3-yl,6-(3-hydroxypropoxy)-(2- or 4-)methylpyridin-3-yl,6-(2,3-dihydroxypropoxy)-(2- or 4-)methylpyridin-3-yl,6-((2R)-2,3-dihydroxypropoxy)-(2- or 4-)methylpyridin-3-yl,6-((2S)-2,3-dihydroxypropoxy)-(2- or 4-)methylpyridyl-3-yl,6-((3S)-3-hydroxybutoxy)-(2- or 4-)methylpyridyl-3-yl,6-((3R)-3-hydroxybutoxy)-(2- or 4-)methylpyridyl-3-yl,6-(3-hydroxy-3-methylbutoxy)-(2- or 4-)methylpyridin-3-yl,6-(3-hydroxy-2-hydroxymethylpropoxy)-(2- or 4-)methylpyridin-3-yl,

6-(3-hydroxy-2-hydroxymethyl-2-methylpropoxy)-(2- or4-)methylpyridin-3-yl, 6-(3-hydroxybutoxy)-(2- or 4-)methylpyridin-3-yl,6-(2-ethoxyethoxy)-(2- or 4-)methylpyridin-3-yl,6-(2-methylsulfonylethoxy)-(2- or 4-)methylpyridin-3-yl,6-(3-methylsulfonyl-propoxy)-(2- or 4-)methylpyridin-3-yl,6-((1,1-dioxidetetrahydro-2H-thiopyran-4-yl)oxy)-(2- or4-)methylpyridin-3-yl,6-((4-hydroxy-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)methoxy)-(2- or4-)methylpyridin-3-yl, 6-((3-methyloxetane-3-yl)methoxy)-(2- or4-)methylpyridin-3-yl, 6-(2-hydroxyethoxy)-(2,4-, 2,5-, or4,5-)dimethylpyridin-3-yl, 6-(3-hydroxypropoxy)-(2,4-, 2,5-, or4,5-)dimethylpyridin-3-yl, 6-(2,3-dihydroxypropoxy)-(2,4-, 2,5-, or4,5-)dimethylpyridin-3-yl, 6-(3-hydroxy-2-hydroxymethylpropoxy)-(2,4-,2,5-, or 4,5-)dimethylpyridin-3-yl,6-(3-hydroxy-2-hydroxymethyl-2-methylpropoxy)-(2,4-, 2,5-, or4,5-)dimethylpyridin-3-yl, 6-(3-hydroxybutoxy)-(2,4-, 2,5-, or4,5-)dimethylpyridin-3-yl, 6-(3-hydroxy-3-methylbutoxy)-(2,4-, 2,5-, or4,5-)dimethylpyridin-3-yl, 6-(2-ethoxyethoxy)-(2,4-, 2,5-, or4,5-)dimethylpyridin-3-yl, 6-(2-methylsulfonylethoxy)-(2,4-, 2,5-, or4,5-)dimethylpyridin-3-yl, 6-(3-methylsulfonyl-propoxy)-(2,4-, 2,5-, or4,5-)dimethylpyridin-3-yl,6-((1,1-dioxidetetrahydro-2H-thiopyran-4-yl)oxy)-(2,4-, 2,5-, or4,5-)dimethylpyridin-3-yl,6-((4-hydroxy-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)methoxy)-(2,4-,2,5-, or 4,5-)dimethylpyridin-3-yl,6-((3-methyloxetane-3-yl)methoxy)-(2,4-, 2,5-, or4,5-)dimethylpyridin-3-yl, 6-(3-hydroxy-3-methylbutoxy)-(2- or4-)methoxypyridin-3-yl, 6-(2-aminoethoxy)-(2- or 4-)methylpyridin-3-yl,6-(2-aminoethoxy)-(2,4-, 2,5-, or 4,5-)dimethylpyridin-3-yl,6-(3-aminopropoxy)-(2- or 4-)methylpyridin-3-yl,6-(3-aminopropoxy)-(2,4-, 2,5-, or 4,5-)dimethylpyridin-3-yl,6-(2-acetylamino-ethoxy)-(2- or 4-)methylpyridin-3-yl,6-(2-acetylamino-ethoxy)-(2,4-, 2,5-, or 4,5-)dimethylpyridin-3-yl,6-(3-acetylamino-propoxy)-(2- or 4-)methylpyridin-3-yl,6-(3-acetylamino-propoxy)-(2,4-, 2,5-, or 4,5-)dimethylpyridin-3-yl,6-(2-methylsulfonylamino-ethoxy)-(2- or 4-)methylpyridin-3-yl,6-(2-methylsulfonylamino-ethoxy)-(2,4-, 2,5-, or4,5-)dimethylpyridin-3-yl, 6-(3-methylsulfonylamino-propoxy)-(2- or4-)methylpyridin-3-yl, 6-(3-methylsulfonylamino-propoxy)-(2,4-, 2,5-, or4,5-)dimethylpyridin-3-yl, 6-(2-carbamoyl-ethoxy)-(2- or4-)methylpyridin-3-yl, 6-(2-carbamoyl-ethoxy)-(2,4-, 2,5-, or4,5-)dimethylpyridin-3-yl, 6-(3-carbamoyl-propoxy)-(2- or4-)methylpyridin-3-yl,

6-(3-carbamoyl-propoxy)-(2,4-, 2,5-, or 4,5-)dimethylpyridin-3-yl,6-(2-methylcarbamoyl-ethoxy)-(2- or 4-)methylpyridin-3-yl,6-(2-methylcarbamoyl-ethoxy)-(2,4-, 2,5-, or 4,5-)dimethylpyridin-3-yl,6-(3-methylcarbamoyl-propoxy)-(2- or 4-)methylpyridin-3-yl,6-(3-methylcarbamoyl-propoxy)-(2,4-, 2,5-, or 4,5-)dimethylpyridin-3-yl,6-(2-dimethylcarbamoyl-ethoxy)-(2- or 4-)methylpyridin-3-yl,6-(2-dimethylcarbamoyl-ethoxy)-(2,4-, 2,5-, or4,5-)dimethylpyridin-3-yl, 6-(3-dimethylcarbamoyl-propoxy)-(2- or4-)methylpyridin-3-yl, 6-(3-dimethylcarbamoyl-propoxy)-(2,4-, 2,5-, or4,5-)dimethylpyridin-3-yl, 6-(2-sulfamoyl-ethoxy)-(2- or4-)methylpyridin-3-yl, 6-(2-sulfamoyl-ethoxy)-(2,4-, 2,5-, or4,5-)dimethylpyridin-3-yl, 6-(3-sulfamoyl-propoxy)-(2- or4-)methylpyridin-3-yl, 6-(3-sulfamoyl-propoxy)-(2,4-, 2,5-, or4,5-)dimethylpyridin-3-yl, 6-(2-methylsulfamoyl-ethoxy)-(2- or4-)methylpyridin-3-yl, 6-(2-methylsulfamoyl-ethoxy)-(2,4-, 2,5-, or4,5-)dimethylpyridin-3-yl, 6-(3-methylsulfamoyl-propoxy)-(2- or4-)methylpyridin-3-yl, 6-(3-methylsulfamoyl-propoxy)-(2,4-, 2,5-, or4,5-)dimethylpyridin-3-yl, 6-(2-dimethylsulfamoyl-ethoxy)-(2- or4-)methylpyridin-3-yl, 6-(2-dimethylsulfamoyl-ethoxy)-(2,4-, 2,5-, or4,5-)dimethylpyridin-3-yl, 6-(3-dimethylsulfamoyl-propoxy)-(2- or4-)methylpyridin-3-yl, 6-(3-dimethylsulfamoyl-propoxy)-(2,4-, 2,5-, or4,5-)dimethylpyridin-3-yl, 6-(2-(2-oxo-1-pyrrolidinyl)ethoxy)-(2- or4-)methylpyridin-3-yl, 6-(2-(2-oxo-1-pyrrolidinyl)ethoxy)-(2,4-, 2,5-,or 4,5-)dimethylpyridin-3-yl, 6-(3-(2-oxo-1-pyrrolidinyl)propoxy)-(2- or4-)methylpyridin-3-yl, 6-(3-(2-oxo-1-pyrrolidinyl)propoxy)-(2,4-, 2,5-,or 4,5-)dimethylpyridin-3-yl, 6-(1-piperidinyl)pyridin-3-yl,6-(4-morpholino)pyridin-3-yl, 6-(4-morpholino)-(2,4-, 2,5-, or4,5-)dimethylpyridin-3-yl, 6-acetylpyridin-3-yl,6-benzyloxypyridin-3-yl, 6-methylsulfonylpyridin-3-yl,6-carbamoylpyridin-3-yl, (2- or 4-)methoxypyrimidin-5-yl,2-(3-hydroxy-3-methylbutoxy)-4-methylpyrimidin-5-yl,2-(3-methylsulfonyl-propoxy)-4-methylpyrimidin-5-yl,2-(3-hydroxy-3-methylbutoxy)-4,6-dimethylpyrimidin-5-yl,2-(3-methylsulfonyl-propoxy)-4,6-dimethylpyrimidin-5-yl,

2-(4-morpholino)-4,6-dimethylpyrimidin-5-yl,2-ethyl-6,7-difluoro-1H-benzimidazol-1-yl,2-ethoxy-6,7-difluoro-1H-benzimidazol-1-yl, (2-, 4-, 5-, 6-, 7-, or 8-)methylquinoline-3-yl, 6-(1-piperidinyl)pyridin-3-yl,1-methylpiperidin-4-yl, and 4,4-difluoropiperidin-1-yl.

The “aralkyl group which is optionally substituted with 1 to 5substituent(s) RII” is the “aralkyl group” in which any hydrogen atom isoptionally substituted with 1 to 5 substituent(s) RII. That is to say,the “aralkyl group which is optionally substituted with 1 to 5substituent(s) RII” includes, in addition to the unsubstituted groupsexemplified as the “aralkyl group”: “an aralkyl group which issubstituted with 1 to 5 group(s) optionally selected from a halogenatom, —OH, a cyano group, a C₁₋₆ alkoxy group (the C₁₋₆ alkoxy group isoptionally substituted with 1 to 5 halogen atom(s), 1 to 5 —OH, 1 to 5C₁₋₆ alkoxy group(s), 1 to 5 aryl group(s) (the aryl group is optionallysubstituted with 1 to 3 halogen atom(s)), 1 to 5 heterocyclic group(s)(the heterocyclic group is optionally substituted with 1 to 3 C₁₋₆ alkylgroup(s) or 1 to 3 oxo group(s)), 1 to 5 —S(O)_(i)R^(a) (i is an integerof 0 to 2) group(s), 1 to 5 —SO₂NR^(d)R^(e) group(s), 1 to 5—CONR^(d)R^(e) group(s), or 1 to 5 —NR^(b1)R^(c1) group(s)), a—NR^(b1)R^(c1) group, a heterocyclic oxy group (the heterocyclic oxygroup is optionally substituted with 1 to 3 C₁₋₆ alkyl group(s) or 1 to3 oxo group(s)), a C₁₋₆ alkyl group (the C₁₋₆ alkyl group is optionallysubstituted with 1 to 5 halogen atom(s), 1 to 5 —OH, 1 to 5 C₁₋₆ alkoxygroup(s), 1 to 5 —S(O)_(i)R^(a) (i is an integer of 0 to 2) group(s), 1to 5 —SO₂NR^(d)R^(e) group(s), 1 to 5—CONR^(d)R^(e) group(s), or 1 to 5—NR^(b1)R^(c1) group(s)), a C₂₋₆ alkenyl group, a C₂₋₇ alkanoyl group,an aralkyloxy group, a heterocyclic group (the heterocyclic group isoptionally substituted with 1 to 3 C₁₋₆ alkyl group(s) or 1 to 3 oxogroup(s)), a heterocyclic carbonyl group (the heterocyclic carbonylgroup is optionally substituted with 1 to 3 C₁₋₆ alkyl group(s) or 1 to3 oxo group(s)), a —S(O)_(i)R^(a) (i is an integer of 0 to 2) group, a—CONR^(d)R^(e) group, and a —CONR^(d)R^(e1) group”. The substituent(s)of the aralkyl group may be substituted with either the aryl moiety orthe alkyl moiety. Specific examples thereof include, in addition tounsubstituted benzyl, phenethyl, 1-naphthylmethyl, or 2-naphthylmethyl:(2-, 3-, or 4-)fluorobenzyl, (2-, 3-, or 4-)chlorobenzyl, (2-, 3-, or4-)hydroxybenzyl, (2-, 3-, or 4-)methoxybenzyl, (2-, 3-, or4-)trifluoromethoxybenzyl, (2-, 3-, or 4-)methylbenzyl, (2-, 3-, or4-)trifluoromethylbenzyl, (2,6-, 2,5-, 2,4-, or 2,3-)dimethylbenzyl,3,5-ditrifluoromethylbenzyl, 4-(2-hydroxyethoxy)-2,6-dimethylbenzyl,4-(2,3-dihydroxypropoxy)-2,6-dimethylbenzyl, and4-(3-hydroxy-3-methylbutoxy)-2,6-dimethylbenzyl.

The “heteroarylalkyl group which is optionally substituted with 1 to 5substituent(s) RII” is the “heteroarylalkyl group” in which any hydrogenatom is optionally substituted with 1 to 5 substituent(s) RII. That isto say, the “heteroarylalkyl group which is optionally substituted with1 to 5 substituent(s) RII” includes, in addition to the unsubstitutedgroups exemplified as the “heteroarylalkyl group”: “a heteroarylalkylgroup which is substituted with 1 to 5 group(s) optionally selected froma halogen atom, —OH, a cyano group, a C₁₋₆ alkoxy group (the C₁₋₆ alkoxygroup is optionally substituted with 1 to 5 halogen atom(s), 1 to 5 —OH,1 to 5 C₁₋₆ alkoxy group(s), 1 to 5 aryl group(s) (the aryl group isoptionally substituted with 1 to 3 halogen atom(s)), 1 to 5 heterocyclicgroup(s) (the heterocyclic group is optionally substituted with 1 to 3C₁₋₆ alkyl group(s) or 1 to 3 oxo group(s)), 1 to 5 —S(O)_(i)R^(a) (i isan integer of 0 to 2) group(s), 1 to 5 —SO₂NR^(d)R^(e) group(s), 1 to 5—CONR^(d)R^(e) group(s), or 1 to 5 —NR^(b1)R^(c1) group(s)), a—NR^(b1)R^(c1) group, a heterocyclic oxy group (the heterocyclic oxygroup is optionally substituted with 1 to 3 C₁₋₆ alkyl group(s) or 1 to3 oxo group(s)), a C₁₋₆ alkyl group (the C₁₋₆ alkyl group is optionallysubstituted with 1 to 5 halogen atom(s), 1 to 5 —OH, 1 to 5 C₁₋₆ alkoxygroup(s), 1 to 5 —S(O)_(i)R^(a) (i is an integer of 0 to 2) group(s), 1to 5 —SO₂NR^(d)R^(e) group(s), 1 to 5 —CONR^(d)R^(e) group(s), or 1 to 5—NR^(b1)R^(c1) group(s)), a C₂₋₆ alkenyl group, a C₂₋₇ alkanoyl group,an aralkyloxy group, a heterocyclic group (the heterocyclic group isoptionally substituted with 1 to 3 C₁₋₆ alkyl group(s) or 1 to 3 oxogroup(s)), a heterocyclic carbonyl group (the heterocyclic carbonylgroup is optionally substituted with 1 to 3 C₁₋₆ alkyl group(s) or 1 to3 oxo group(s)), a —S(O)_(i)R^(a) (i is an integer of 0 to 2) group, a—CONR^(d)R^(e) group, and a —CONR^(d)R^(e1) group”. The substituent(s)of the heteroarylalkyl group may be substituted with either theheteroaryl moiety or the alkyl moiety. Specific examples thereofinclude, in addition to unsubstituted pyrrolylmethyl, furylmethyl,pyridylmethyl, or quinolylmethyl: (2-, 4-, 5-, or6-)chloropyridin-3-ylmethyl, (2-, 4-, 5-, or6-)hydroxypyridin-3-ylmethyl, (2-, 4-, 5-, or6-)methoxypyridin-3-ylmethyl, (2-, 4-, 5-, or6-)methylpyridin-3-ylmethyl, (2,4-, 2,5-, 2,6-, 4,5-, or4,6-)dimethylpyridin-3-ylmethyl,6-(2-hydroxyethoxy)-2,4-dimethylpyridin-3-ylmethyl,6-(2,3-dihydroxypropoxy)-2,4-dimethylpyridin-3-ylmethyl, and6-(3-hydroxy-3-methylbutoxy)-2,4-dimethylpyridin-3-ylmethyl.

The “non-aromatic heterocyclic alkyl group which is optionallysubstituted with 1 to 5 substituent(s) RII” is the “non-aromaticheterocyclic alkyl group” in which any hydrogen atom is optionallysubstituted with 1 to 5 substituent(s) RII. That is to say, the“non-aromatic heterocyclic alkyl group which is optionally substitutedwith 1 to 5 substituent(s) RII” includes, in addition to theunsubstituted groups exemplified as the “non-aromatic heterocyclic alkylgroup”: “a non-aromatic heterocyclic alkyl group which is substitutedwith 1 to 5 group(s) optionally selected from a halogen atom, —OH, acyano group, a C₁₋₆ alkoxy group (the C₁₋₆ alkoxy group is optionallysubstituted with 1 to 5 halogen atom(s), 1 to 5 —OH, 1 to 5 C₁₋₆ alkoxygroup(s), 1 to 5 aryl group(s) (the aryl group is optionally substitutedwith 1 to 3 halogen atom(s)), 1 to 5 heterocyclic group(s) (theheterocyclic group is optionally substituted with 1 to 3 C₁₋₆ alkylgroup(s) or 1 to 3 oxo group(s)), 1 to 5 —S(O)_(i)R^(a) (i is an integerof 0 to 2) group(s), 1 to 5 —SO₂NR^(d)R^(e) group(s), 1 to 5—CONR^(d)R^(e) group(s), or 1 to 5 —NR^(b1)R^(c1) group(s)), a—NR^(b1)R^(c1) group, a heterocyclic oxy group (the heterocyclic oxygroup is optionally substituted with 1 to 3 C₁₋₆ alkyl group(s) or 1 to3 oxo group(s)), a C₁₋₆ alkyl group (the C₁₋₆ alkyl group is optionallysubstituted with 1 to 5 halogen atom(s), 1 to 5 —OH, 1 to 5 C₁₋₆ alkoxygroup(s), 1 to 5 —S(O)_(i)R^(a) (i is an integer of 0 to 2) group(s), 1to 5 —SO₂NR^(d)R^(e) group(s), 1 to 5 —CONR^(d)R^(e) group(s), or 1 to 5—NR^(b1)R^(c1) group(s)), a C₂₋₆ alkenyl group, a C₂₋₇ alkanoyl group,an aralkyloxy group, a heterocyclic group (the heterocyclic group isoptionally substituted with 1 to 3 C₁₋₆ alkyl group(s) or 1 to 3 oxogroup(s)), a heterocyclic carbonyl group (the heterocyclic carbonylgroup is optionally substituted with 1 to 3 C₁₋₆ alkyl group(s) or 1 to3 oxo group(s)), a —S(O)_(i)R^(a) (i is an integer of 0 to 2) group, a—CONR^(d)R^(e) group, and a —CONR^(d)R^(e1) group”. The substituent(s)of the non-aromatic heterocyclic alkyl group may be substituted witheither the non-aromatic heterocyclic moiety or the alkyl moiety.Specific examples thereof include, in addition to unsubstitutedpyrrolidinylmethyl, tetrahydrofurylmethyl, piperidinylmethyl, ortetrahydropyranylmethyl: (2-, 3-, or 4-)chloropiperidin-1-ylmethyl, (2-,3-, or 4-)hydroxypiperidin-1-ylmethyl, (2-, 3-, or4-)cyanopiperidin-1-ylmethyl, (2-, 3-, or4-)methoxypiperidin-1-ylmethyl, (2-, 3-, or4-)methylpiperidin-1-ylmethyl, (2,3-, 2,4-, 2,5-, 2,6-, 3,4-, or3,5-)dimethylpiperidin-1-ylmethyl,4-(2-hydroxyethoxy)-2,6-dimethylpiperidin-1-ylmethyl,4-(2,3-dihydroxypropoxy)-2,6-dimethylpiperidin-1-ylmethyl, and4-(3-hydroxy-3-methylbutoxy)-2,6-dimethylpiperidin-1-ylmethyl.

The “aryloxy group which is optionally substituted with 1 to 5substituent(s) RII” is the “aryloxy group” in which any hydrogen atom isoptionally substituted with 1 to 5 substituent(s) RII. The “aryloxygroup which is optionally substituted with 1 to 5 substituent(s) RII” isalso the “aryl group which is optionally substituted with 1 to 5substituent(s) RII” which is substituted with an oxygen atom. That is tosay, the “aryloxy group which is optionally substituted with 1 to 5substituent(s) RII” includes, in addition to the unsubstituted groupsexemplified as the “aryloxy group”: “an aryloxy group which issubstituted with 1 to 5 group(s) optionally selected from a halogenatom, —OH, a cyano group, a C₁₋₆ alkoxy group (the C₁₋₆ alkoxy group isoptionally substituted with 1 to 5 halogen atom(s), 1 to 5 —OH, 1 to 5C₁₋₆ alkoxy group(s), 1 to 5 aryl group(s) (the aryl group is optionallysubstituted with 1 to 3 halogen atom(s)), 1 to 5 heterocyclic group(s)(the heterocyclic group is optionally substituted with 1 to 3 C₁₋₆ alkylgroup(s) or 1 to 3 oxo group(s)), 1 to 5 —S(O)_(i)R^(a) (i is an integerof 0 to 2) group(s), 1 to 5 —SO₂NR^(d)R^(e) group(s), 1 to5—CONR^(d)R^(e) group(s), or 1 to 5 —NR^(b1)R^(c1) group(s)), a—NR^(b1)R^(c1) group, a heterocyclic oxy group (the heterocyclic oxygroup is optionally substituted with 1 to 3 C₁₋₆ alkyl group(s) or 1 to3 oxo group(s)), a C₁₋₆ alkyl group (the C₁₋₆ alkyl group is optionallysubstituted with 1 to 5 halogen atom(s), 1 to 5—OH, 1 to 5 C₁₋₆ alkoxygroup(s), 1 to 5 —S(O)_(i)R^(a) (i is an integer of 0 to 2) group(s), 1to 5 —SO₂NR^(d)R^(e) group(s), 1 to 5 —CONR^(d)R^(e) group(s), or 1 to 5—NR^(b1)R^(c1) group(s)), a C₂₋₆ alkenyl group, a C₂₋₇ alkanoyl group,an aralkyloxy group, a heterocyclic group (the heterocyclic group isoptionally substituted with 1 to 3 C₁₋₆ alkyl group(s) or 1 to 3 oxogroup(s)), a heterocyclic carbonyl group (the heterocyclic carbonylgroup is optionally substituted with 1 to 3 C₁₋₆ alkyl group(s) or 1 to3 oxo group(s)), a —S(O)_(i)R^(a) (i is an integer of 0 to 2) group, a—CONR^(d)R^(e) group, and a —CONR^(d)R^(e1) group”. Specific examplesthereof include a group in which the group exemplified specifically asthe “aryl group which is optionally substituted with 1 to 5substituent(s) RII” is substituted with an oxygen atom, such as, inaddition to unsubstituted phenoxy, 1-naphthyloxy, 2-naphthyloxy,1-indanyloxy, or 2-indanyloxy: (2-, 3-, or 4-)fluorophenoxy, (2-, 3-, or4-)chlorophenoxy, (2-, 3-, or 4-)hydroxyphenoxy, (2-, 3-, or4-)cyanophenoxy, (2-, 3-, or 4-)methoxyphenoxy, (2-, 3-, or4-)trifluoromethoxyphenoxy, (2-, 3-, or 4-)methylphenoxy, (2-, 3-, or4-)trifluoromethylphenoxy, (2,6-, 2,5-, 2,4-, or 2,3-)dimethylphenoxy,(3- or 4-)(2-hydroxyethyl)phenoxy, 4-(2-hydroxyethoxy)phenoxy,4-(2,3-dihydroxypropoxy)phenoxy, (3- or4-)(3-hydroxy-3-methylbutoxy)phenoxy, (3- or4-)(2-ethoxy-ethoxy)phenoxy, (3- or4-)(3-methylsulfonyl-propoxy)phenoxy,4-(3-hydroxy-3-methylbutoxy)-2-methylphenoxy,4-(2-ethoxy-ethoxy)-2-methylphenoxy,4-(3-methylsulfonyl-propoxy)-2-methylphenoxy,4-(2-hydroxyethoxy)-2,6-dimethylphenoxy,4-(2,3-dihydroxypropoxy)-2,6-dimethylphenoxy,4-(3-hydroxy-3-methylbutoxy)-2,6-dimethylphenoxy,4-(2-ethoxy-ethoxy)-2,6-dimethylphenoxy,4-(3-methylsulfonyl-propoxy)-2,6-dimethylphenoxy,4-methylsulfonylphenoxy, and 4-(4-morpholino)phenoxy.

The “heteroaryloxy group which is optionally substituted with 1 to 5substituent(s) RII” is the “heteroaryloxy group” in which any hydrogenatom is optionally substituted with 1 to 5 substituent(s) RII. The“heteroaryloxy group which is optionally substituted with 1 to 5substituent(s) RII” is also a group in which a group having the“heteroaryl group” in the “heterocyclic group which is optionallysubstituted with 1 to 5 substituent(s) RII” is substituted with anoxygen atom. That is to say, the “heteroaryloxy group which isoptionally substituted with 1 to 5 substituent(s) RII” includes, inaddition to the unsubstituted groups exemplified as the “heteroaryloxygroup”: “a heteroaryloxy group which is substituted with 1 to 5 group(s)optionally selected from a halogen atom, —OH, a cyano group, a C₁₋₆alkoxy group (the C₁₋₆ alkoxy group is optionally substituted with 1 to5 halogen atom(s), 1 to 5 —OH, 1 to 5 C₁₋₆ alkoxy group(s), 1 to 5 arylgroup(s) (the aryl group is optionally substituted with 1 to 3 halogenatom(s)), 1 to 5 heterocyclic group(s) (the heterocyclic group isoptionally substituted with 1 to 3 C₁₋₆ alkyl group(s) or 1 to 3 oxogroup(s)), 1 to 5 —S(O)_(i)R^(a) (i is an integer of 0 to 2) group(s), 1to 5 —SO₂NR^(d)R^(e) group(s), 1 to 5 —CONR^(d)R^(e) group(s), or 1 to 5—NR^(b1)R^(c1) group(s)), a —NR^(b1)R^(c1) group, a heterocyclic oxygroup (the heterocyclic oxy group is optionally substituted with 1 to 3C₁₋₆ alkyl group(s) or 1 to 3 oxo group(s)), a C₁₋₆ alkyl group (theC₁₋₆ alkyl group is optionally substituted with 1 to 5 halogen atom(s),1 to 5—OH, 1 to 5 C₁₋₆ alkoxy group(s), 1 to 5 —S(O)_(i)R^(a) (i is aninteger of 0 to 2) group(s), 1 to 5 —SO₂NR^(d)R^(e) group(s), 1 to 5—CONR^(d)R^(e) group(s), or 1 to 5 —NR^(b1)R^(c1) group(s)), a C₂₋₆alkenyl group, a C₂₋₇ alkanoyl group, an aralkyloxy group, aheterocyclic group (the heterocyclic group is optionally substitutedwith 1 to 3 C₁₋₆ alkyl group(s) or 1 to 3 oxo group(s)), a heterocycliccarbonyl group (the heterocyclic carbonyl group is optionallysubstituted with 1 to 3 C₁₋₆ alkyl group(s) or 1 to 3 oxo group(s)), a—S(O)_(i)R^(a) (i is an integer of 0 to 2) group, a —CONR^(d)R^(e)group, and a —CONR^(d)R^(e1) group”. Specific examples thereof include agroup in which a group having the “heteroaryl group” among the groupsexemplified specifically as the “heterocyclic group which is optionallysubstituted with 1 to 5 substituent(s) RII” is substituted with anoxygen atom, such as, in addition to pyrrolyloxy, furyloxy, thienyloxy,(2-, 3-, or 4-)pyridyloxy, pyrimidinyloxy, or quinolyloxy: (2-, 4-, 5-,or 6-)chloropyridin-3-yloxy, (2- or 3-)chloropyridin-4-yloxy, (2-, 4-,5-, or 6-)hydroxypyridin-3-yloxy, (2- or 3-)hydroxypyridin-4-yloxy, (3-,4-, 5-, or 6-)cyanopyridin-2-yloxy, (2-, 4-, 5-, or6-)cyanopyridin-3-yloxy, (2- or 3-)cyanopyridin-4-yloxy, (2-, 4-, 5-, or6-)methoxypyridin-3-yloxy, (2- or 3-)methoxypyridin-4-yloxy, (2-, 4-,5-, or 6-)methylpyridin-3-yloxy, (2- or 3-)methylpyridin-4-yloxy, (2,4-,2,5-, 2,6-, 4,5-, or 4,6-)dimethylpyridin-3-yloxy, (2,3-, 2,5-, 2,6-, or3,5-)dimethylpyridin-4-yloxy, 6-methoxy-(2-, 4-, or5-)methylpyridin-3-yloxy, 6-(2-hydroxyethoxy)pyridin-3-yloxy,6-(2,3-dihydroxypropoxy)pyridin-3-yloxy,6-(3-hydroxy-3-methylbutoxy)pyridin-3-yloxy,6-(2-ethoxyethoxy)pyridin-3-yloxy,6-(3-methylsulfonyl-propoxy)pyridin-3-yloxy,6-(3-hydroxy-3-methylbutoxy)-(2- or 4-)methylpyridin-3-yloxy,6-(2-ethoxyethoxy)-(2- or 4-)methylpyridin-3-yloxy,6-(3-methylsulfonyl-propoxy)-(2- or 4-)methylpyridin-3-yloxy,6-(2-hydroxyethoxy)-2,4-dimethylpyridin-3-yloxy,6-(2,3-dihydroxypropoxy)-2,4-dimethylpyridin-3-yloxy,6-(3-hydroxy-3-methylbutoxy)-2,4-dimethylpyridin-3-yloxy,6-(2-ethoxyethoxy)-2,4-dimethylpyridin-3-yloxy,6-(3-methylsulfonyl-propoxy)-2,4-dimethylpyridin-3-yloxy, and6-(4-morpholino)-pyridin-3-yloxy.

The “non-aromatic heterocyclic oxy group which is optionally substitutedwith 1 to 5 substituent(s) RII” is the “non-aromatic heterocyclic oxygroup” in which any hydrogen atom is optionally substituted with 1 to 5substituent(s) RII. That is to say, the “non-aromatic heterocyclic oxygroup which is optionally substituted with 1 to 5 substituent(s) RII”includes, in addition to the unsubstituted groups exemplified as the“non-aromatic heterocyclic oxy group”: “a non-aromatic heterocyclic oxygroup which is substituted with 1 to 5 group(s) optionally selected froma halogen atom, —OH, a cyano group, a C₁₋₆ alkoxy group (the C₁₋₆ alkoxygroup is optionally substituted with 1 to 5 halogen atom(s), 1 to 5 —OH,1 to 5 C₁₋₆ alkoxy group(s), 1 to 5 aryl group(s) (the aryl group isoptionally substituted with 1 to 3 halogen atom(s)), 1 to 5 heterocyclicgroup(s) (the heterocyclic group is optionally substituted with 1 to 3C₁₋₆ alkyl group(s) or 1 to 3 oxo group(s)), 1 to 5 —S(O)_(i)R^(a) (i isan integer of 0 to 2) group(s), 1 to 5 —SO₂NR^(d)R^(e) group(s), 1 to 5—CONR^(d)R^(e) group(s), or 1 to 5 —NR^(b1)R^(c1) group(s)), a—NR^(b1)R^(c1) group, a heterocyclic oxy group (the heterocyclic oxygroup is optionally substituted with 1 to 3 C₁₋₆ alkyl group(s) or 1 to3 oxo group(s)), a C₁₋₆ alkyl group (the C₁₋₆ alkyl group is optionallysubstituted with 1 to 5 halogen atom(s), 1 to 5 —OH, 1 to 5 C₁₋₆ alkoxygroup(s), 1 to 5 —S(O)_(i)R^(a) (i is an integer of 0 to 2) group(s), 1to 5 —SO₂NR^(d)R^(e) group(s), 1 to 5 —CONR^(d)R^(e) group(s), or 1 to 5—NR^(b1)R^(c1) group(s)), a C₂₋₆ alkenyl group, a C₂₋₇ alkanoyl group,an aralkyloxy group, a heterocyclic group (the heterocyclic group isoptionally substituted with 1 to 3 C₁₋₆ alkyl group(s) or 1 to 3 oxogroup(s)), a heterocyclic carbonyl group (the heterocyclic carbonylgroup is optionally substituted with 1 to 3 C₁₋₆ alkyl group(s) or 1 to3 oxo group(s)), a —S(O)_(i)R^(a) (i is an integer of 0 to 2) group, a—CONR^(d)R^(e) group, and a —CONR^(d)R^(e1) group”. For example, a 3- to8-membered saturated or unsaturated non-aromatic heterocyclic oxy groupoptionally substituted with 1 to 5 substituent(s) RII is included.Examples thereof include, in addition to pyrrolidinyloxy,tetrahydrofuryloxy, piperidinyloxy, dihydropyranyloxy, ortetrahydropyranyloxy(oxanyloxy): (2- or 3-)fluorooxane-4-yloxy, (2- or3-)chlorooxane-4-yloxy, (2- or 3-)hydroxyoxane-4-yloxy, (2- or3-)methoxyoxane-4-yloxy, (2- or 3-)trifluoromethoxyoxane-4-yloxy, (2- or3-)methyloxane-4-yloxy, (2- or 3-)trifluoromethyloxane-4-yloxy, (2,3-,2,5-, 2,6-, or 3,5-)dimethyloxane-4-yloxy, 1-methylpiperidin-4-yloxy,and (1,2- or 1,3-)dimethylpiperidin-4-yloxy.

The “aralkyloxy group which is optionally substituted with 1 to 5substituent(s) RII” is the “aralkyloxy group” in which any hydrogen atomis optionally substituted with 1 to 5 substituent(s) RII. That is tosay, the “aralkyloxy group which is optionally substituted with 1 to 5substituent(s) RII” includes, in addition to the unsubstituted groupsexemplified as the “aralkyloxy group”: “an aralkyloxy group which issubstituted with 1 to 5 group(s) optionally selected from a halogenatom, —OH, a cyano group, a C₁₋₆ alkoxy group (the C₁₋₆ alkoxy group isoptionally substituted with 1 to 5 halogen atom(s), 1 to 5 —OH, 1 to 5C₁₋₆ alkoxy group(s), 1 to 5 aryl group(s) (the aryl group is optionallysubstituted with 1 to 3 halogen atom(s)), 1 to 5 heterocyclic group(s)(the heterocyclic group is optionally substituted with 1 to 3 C₁₋₆ alkylgroup(s) or 1 to 3 oxo group(s)), 1 to 5 —S(O)_(i)R^(a) (i is an integerof 0 to 2) group(s), 1 to 5 —SO₂NR^(d)R^(e) group(s), 1 to 5—CONR^(d)R^(e) group(s), or 1 to 5 —NR^(b1)R^(c1) group(s)), a—NR^(b1)R^(c1) group, a heterocyclic oxy group (the heterocyclic oxygroup is optionally substituted with 1 to 3 C₁₋₆ alkyl group(s) or 1 to3 oxo group(s)), a C₁₋₆ alkyl group (the C₁₋₆ alkyl group is optionallysubstituted with 1 to 5 halogen atom(s), 1 to 5 —OH, 1 to 5 C₁₋₆ alkoxygroup(s), 1 to 5 —S(O)_(i)R^(a) (i is an integer of 0 to 2) group(s), 1to 5 —SO₂NR^(d)R^(e) group(s), 1 to 5 —CONR^(d)R^(e) group(s), or 1 to 5—NR^(b1)R^(c1) group(s)), a C₂₋₆ alkenyl group, a C₂₋₇ alkanoyl group,an aralkyloxy group, a heterocyclic group (the heterocyclic group isoptionally substituted with 1 to 3 C₁₋₆ alkyl group(s) or 1 to 3 oxogroup(s)), a heterocyclic carbonyl group (the heterocyclic carbonylgroup is optionally substituted with 1 to 3 C₁₋₆ alkyl group(s) or 1 to3 oxo group(s)), a —S(O)_(i)R^(a) (i is an integer of 0 to 2) group, a—CONR^(d)R^(e) group, and a —CONR^(d)R^(e1) group”. The substituent(s)of the aralkyloxy group may be substituted with the aryl moiety or thealkyl moiety. Specific examples thereof include, in addition tobenzyloxy, phenethyloxy, 1-naphthylmethoxy, or 2-naphthylmethoxy: (2-,3-, or 4-)fluorobenzyloxy, (2-, 3-, or 4-)chlorobenzyloxy, (2-, 3-, or4-)hydroxybenzyloxy, (2-, 3-, or 4-)methoxybenzyloxy, (2-, 3-, or4-)trifluoromethoxybenzyloxy, (2-, 3-, or 4-)methylbenzyloxy, (2-, 3-,or 4-)trifluoromethylbenzyloxy, (2-, 3-, or 4-)methoxyphenethyloxy,(2,6-, 2,5-, 2,4-, or 2,3-)dimethylbenzyloxy,4-(2-hydroxyethoxy)-2,6-dimethylbenzyloxy,4-(2,3-dihydroxypropoxy)-2,6-dimethylbenzyloxy, and4-(3-hydroxy-3-methylbutoxy)-2,6-dimethylbenzyloxy.

The “heteroarylalkyloxy group which is optionally substituted with 1 to5 substituent(s) RII” is the “heteroarylalkyloxy group” in which anyhydrogen atom is optionally substituted with 1 to 5 substituent(s) RII.That is to say, the “heteroarylalkyloxy group which is optionallysubstituted with 1 to 5 substituent(s) RII” includes, in addition to theunsubstituted groups exemplified as the “heteroarylalkyloxy group”: “aheteroarylalkyloxy group which is substituted with 1 to 5 group(s)optionally selected from a halogen atom, —OH, a cyano group, a C₁₋₆alkoxy group (the C₁₋₆ alkoxy group is optionally substituted with 1 to5 halogen atom(s), 1 to 5 —OH, 1 to 5 C₁₋₆ alkoxy group(s), 1 to 5 arylgroup(s) (the aryl group is optionally substituted with 1 to 3 halogenatom(s)), 1 to 5 heterocyclic group(s) (the heterocyclic group isoptionally substituted with 1 to 3 C₁₋₆ alkyl group(s) or 1 to 3 oxogroup(s)), 1 to 5 —S(O)_(i)R^(a) (i is an integer of 0 to 2) group(s), 1to 5 —SO₂NR^(d)R^(e) group(s), 1 to 5 —CONR^(d)R^(e) group(s), or 1 to 5—NR^(b1)R^(c1) group(s)), a —NR^(b1)R^(c1) group, a heterocyclic oxygroup (the heterocyclic oxy group is optionally substituted with 1 to 3C₁₋₆ alkyl group(s) or 1 to 3 oxo group(s)), a C₁₋₆ alkyl group (theC₁₋₆ alkyl group is optionally substituted with 1 to 5 halogen atom(s),1 to 5—OH, 1 to 5 C₁₋₆ alkoxy group(s), 1 to 5 —S(O)_(i)R^(a) (i is aninteger of 0 to 2) group(s), 1 to 5 —SO₂NR^(d)R^(e) group(s), 1 to 5—CONR^(d)R^(e) group(s), or 1 to 5 —NR^(b1)R^(c1) group(s)), a C₂₋₆alkenyl group, a C₂₋₇ alkanoyl group, an aralkyloxy group, aheterocyclic group (the heterocyclic group is optionally substitutedwith 1 to 3 C₁₋₆ alkyl group(s) or 1 to 3 oxo group(s)), a heterocycliccarbonyl group (the heterocyclic carbonyl group is optionallysubstituted with 1 to 3 C₁₋₆ alkyl group(s) or 1 to 3 oxo group(s)), a—S(O)_(i)R^(a) (i is an integer of 0 to 2) group, a —CONR^(d)R^(e)group, and a —CONR^(d)R^(e1) group”. The substituent(s) of theheteroarylalkyloxy group may be substituted with either the heteroarylmoiety or the alkyl moiety. Specific examples thereof include, inaddition to pyrrolylmethoxy, furylmethoxy, pyridylmethoxy, orquinolylmethoxy: (2-, 4-, 5-, or 6-)chloropyridin-3-ylmethoxy, (2-, 4-,5-, or 6-)hydroxypyridin-3-ylmethoxy, (2-, 4-, 5-, or6-)methoxypyridin-3-ylmethoxy, (2-, 4-, 5-, or6-)methylpyridin-3-ylmethoxy, (2,4-, 2,5-, 2,6-, 4,5-, or4,6-)dimethylpyridin-3-ylmethoxy,6-(2-hydroxyethoxy)-2,4-dimethylpyridin-3-ylmethoxy,6-(2,3-dihydroxypropoxy)-2,4-dimethylpyridin-3-ylmethoxy, and6-(3-hydroxy-3-methylbutoxy)-2,4-dimethylpyridin-3-ylmethoxy.

In the compound of Formula (I), in the cyclic amide structure moiety,proton tautomerism shown by the formula below can be generated. Theabundance ratio of this structure can vary depending on whether thecompound of Formula (I) is in the solid state or in the dissolved statein a liquid. The tautomer generated by the cyclic amide moiety isincluded in Formula (I).

Namely, in Formula (I), for example, a proton tautomer as shown below issupposed and such a tautomer is also included in the range of thepresent compound.

For example, when in the cyclic amide structure of Formula (I), n is 1,h is 0, J₁ is CR^(11a), R^(2a), R^(2b), and R^(11a) are a hydrogen atom,and the ring B is bonded to J₁, the tautomerism as shown below issupposed and such a tautomer is also included in the range of thepresent compound.

The description of any specific types of tautomers in any structuralformulae of the present specification is not intended to limit thepresent invention, but is intended to represent the whole set oftautomers that are applicable.

Specifically, for example, a tautomer, namely,5-[4-[[3-[4-(2-ethoxyethoxy)-2,6-dimethylphenyl]phenyl]methoxy]phenyl]-1-oxo-2-isothiazoline-3-ol, of the compounds described as5-[4-[[3-[4-(2-ethoxyethoxy)-2,6-dimethylphenyl]phenyl]methoxy]phenyl]-1-oxo-1,2-thiazolidin-3-one among compounds of Example 1 is also categorized as acompound of Example 1. In addition, a tautomer, namely,5-(4-((3-(2,6-dimethyl-4-(2-ethoxyethoxy)phenyl)phenyl)methoxy)phenyl)-4-isothiazoline-3-one 1-oxide, of the compounds described as5-(4-((3-(2,6-dimethyl-4-(2-ethoxyethoxy)phenyl)phenyl)methoxy)phenyl)isothiazol-3-ol1-oxide among compounds of Step 6 of Example 1, which are a reactionintermediate, is also categorized as a compound of Step 6 of Example 1.

[1-1] In the compound of Formula (I) according to Aspect [1], Ls areindependently a group optionally selected from a halogen atom, —OH, anoxo group, a cyano group, a C₁₋₁₀ alkyl group which is optionallysubstituted with 1 to 5 substituent(s) RI, a C₂₋₁₀ alkenyl group whichis optionally substituted with 1 to 5 substituent(s) RI, a C₂₋₁₀ alkynylgroup which is optionally substituted with 1 to 5 substituent(s) RI, aC₁₋₁₀ alkoxy group which is optionally substituted with 1 to 5substituent(s) RI, a C₂₋₁₀ alkenyloxy group which is optionallysubstituted with 1 to 5 substituent(s) RI, a C₂₋₁₀ alkynyloxy groupwhich is optionally substituted with 1 to 5 substituent(s) RI, an arylgroup which is optionally substituted with 1 to 5 substituent(s) RII, aheterocyclic group which is optionally substituted with 1 to 5substituent(s) RII, an aralkyl group which is optionally substitutedwith 1 to 5 substituent(s) RII, a heteroarylalkyl group which isoptionally substituted with 1 to 5 substituent(s) RII, a non-aromaticheterocyclic alkyl group which is optionally substituted with 1 to 5substituent(s) RII, an aryloxy group which is optionally substitutedwith 1 to 5 substituent(s) RII, a heteroaryloxy group which isoptionally substituted with 1 to 5 substituent(s) RII, a non-aromaticheterocyclic oxy group which is optionally substituted with 1 to 5substituent(s) RII, an aralkyloxy group which is optionally substitutedwith 1 to 5 substituent(s) RII, a heteroarylalkyloxy group which isoptionally substituted with 1 to 5 substituent(s) RII, —SH, —SF₅, a—S(O)_(i)R^(a) (i is an integer of 0 to 2) group, a —NR^(b)R^(c) group,and a substituted spiropiperidinylmethyl group; and

the substituent(s) RI, the substituent(s) RII, i, R^(a), R^(b), andR^(c) are the same as defined in Aspect [1].

[1-1-a] Preferable examples of Ls include a group optionally selectedfrom a halogen atom, a cyano group, a C₁₋₁₀ alkyl group which isoptionally substituted with 1 to 5 substituent(s) RI, a C₂₋₁₀ alkenylgroup which is optionally substituted with 1 to 5 substituent(s) RI, aC₂₋₁₀ alkynyl group which is optionally substituted with 1 to 5substituent(s) RI, a C₁₋₁₀ alkoxy group which is optionally substitutedwith 1 to 5 substituent(s) RI, a C₂₋₁₀ alkenyloxy group which isoptionally substituted with 1 to 5 substituent(s) RI, a C₂₋₁₀ alkynyloxygroup which is optionally substituted with 1 to 5 substituent(s) RI, anaryl group which is optionally substituted with 1 to 5 substituent(s)RII, a heterocyclic group which is optionally substituted with 1 to 5substituent(s) RII, an aralkyl group which is optionally substitutedwith 1 to 5 substituent(s) RII, a heteroarylalkyl group which isoptionally substituted with 1 to 5 substituent(s) RII, a non-aromaticheterocyclic alkyl group which is optionally substituted with 1 to 5substituent(s) RII, an aryloxy group which is optionally substitutedwith 1 to 5 substituent(s) RII, a heteroaryloxy group which isoptionally substituted with 1 to 5 substituent(s) RII, a non-aromaticheterocyclic oxy group which is optionally substituted with 1 to 5substituent(s) RII, an aralkyloxy group which is optionally substitutedwith 1 to 5 substituent(s) RII, a heteroarylalkyloxy group which isoptionally substituted with 1 to 5 substituent(s) RII, a —NR^(b)R^(c)group, and a substituted spiropiperidinylmethyl group (thesubstituent(s) RI and the substituent(s) RII are the same as defined inAspect [1]).

[1-1-b] More preferable examples of Ls include a group optionallyselected from a halogen atom, a cyano group, a C₁₋₁₀ alkyl group whichis optionally substituted with 1 to 5 substituent(s) RI, a C₂₋₁₀ alkenylgroup which is optionally substituted with 1 to 5 substituent(s) RI, aC₁₋₁₀ alkoxy group which is optionally substituted with 1 to 5substituent(s) RI, a C₂₋₁₀ alkenyloxy group which is optionallysubstituted with 1 to 5 substituent(s) RI, an aryl group which isoptionally substituted with 1 to 5 substituent(s) RII, a heterocyclicgroup which is optionally substituted with 1 to 5 substituent(s) RII, anaralkyl group which is optionally substituted with 1 to 5 substituent(s)RII, a heteroarylalkyl group which is optionally substituted with 1 to 5substituent(s) RII, a non-aromatic heterocyclic alkyl group which isoptionally substituted with 1 to 5 substituent(s) RII, an aryloxy groupwhich is optionally substituted with 1 to 5 substituent(s) RII, aheteroaryloxy group which is optionally substituted with 1 to 5substituent(s) RII, a non-aromatic heterocyclic oxy group which isoptionally substituted with 1 to 5 substituent(s) RII, an aralkyloxygroup which is optionally substituted with 1 to 5 substituent(s) RII, aheteroarylalkyloxy group which is optionally substituted with 1 to 5substituent(s) RII, a —NR^(b)R^(c) group, and a substitutedspiropiperidinylmethyl group (the substituent(s) RI and thesubstituent(s) RII are the same as defined in Aspect [1]).

[1-1-c] Further preferable examples of Ls include a group optionallyselected from a halogen atom, a cyano group, a C₁₋₁₀ alkyl group whichis optionally substituted with 1 to 5 substituent(s) RI, a C₂₋₁₀ alkenylgroup which is optionally substituted with 1 to 5 substituent(s) RI, aC₁₋₁₀ alkoxy group which is optionally substituted with 1 to 5substituent(s) RI, a C₂₋₁₀ alkenyloxy group which is optionallysubstituted with 1 to 5 substituent(s) RI, an aryl group which isoptionally substituted with 1 to 5 substituent(s) RII, a heterocyclicgroup which is optionally substituted with 1 to 5 substituent(s) RII, anaralkyl group which is optionally substituted with 1 to 5 substituent(s)RII, a non-aromatic heterocyclic alkyl group which is optionallysubstituted with 1 to 5 substituent(s) RII, an aryloxy group which isoptionally substituted with 1 to 5 substituent(s) RII, a heteroaryloxygroup which is optionally substituted with 1 to 5 substituent(s) RII, anon-aromatic heterocyclic oxy group which is optionally substituted with1 to 5 substituent(s) RII, an aralkyloxy group which is optionallysubstituted with 1 to 5 substituent(s) RII, and a substitutedspiropiperidinylmethyl group (the substituent(s) RI and thesubstituent(s) RII are the same as defined in Aspect [1]).

[1-1-d] Most preferable examples of Ls include a group optionallyselected from a halogen atom, a cyano group, a C₁₋₁₀ alkyl group (theC₁₋₁₀ alkyl group is optionally substituted with 1 to 5 halogen atom(s),1 to 5 —OH, or 1 to 5 C₁₋₄ alkoxy group(s)), a C₂₋₁₀ alkenyl group (theC₂₋₁₀ alkenyl group is optionally substituted with 1 to 5 halogenatom(s), 1 to 5 —OH, or 1 to 5 C₁₋₄ alkoxy group(s)), a C₁₋₁₀ alkoxygroup (the C₁₋₁₀ alkoxy group is optionally substituted with 1 to 5halogen atom(s), 1 to 5 —OH, or 1 to 5 C₁₋₄ alkoxy group(s)), a C₂₋₁₀alkenyloxy group (the C₂₋₁₀ alkenyloxy group is optionally substitutedwith 1 to 5 halogen atom(s), 1 to 5 —OH, or 1 to 5 C₁₋₄ alkoxygroup(s)), an aryl group which is optionally substituted with 1 to 5substituent(s) RIIa, a heterocyclic group which is optionallysubstituted with 1 to 5 substituent(s) RIIa, an aralkyl group which isoptionally substituted with 1 to 5 substituent(s) RIIa, a non-aromaticheterocyclic alkyl group which is optionally substituted with 1 to 5substituent(s) RII, an aryloxy group which is optionally substitutedwith 1 to 5 substituent(s) RIIa, a heteroaryloxy group which isoptionally substituted with 1 to 5 substituent(s) RIIa, a non-aromaticheterocyclic oxy group which is optionally substituted with 1 to 5substituent(s) RIIa, an aralkyloxy group which is optionally substitutedwith 1 to 5 substituent(s) RIIa, and a substitutedspiropiperidinylmethyl group (the substituent(s) RIIa are the same as ordifferent from each other and are each a group optionally selected froma halogen atom, a cyano group, a C₁₋₆ alkoxy group (the C₁₋₆ alkoxygroup is optionally substituted with 1 to 5 halogen atom(s), 1 to 5 —OH,or 1 to 5 C₁₋₄ alkoxy group(s), 1 to 5 non-aromatic heterocyclicgroup(s) (the heterocyclic group is optionally substituted with 1 or 2C₁₋₄ alkyl group(s) or 1 or 2 oxo group(s)), or 1 to 5 —S(O)_(i)R^(a) (iis an integer of 0 to 2) group(s)), a —NR^(b1)R^(c1) group, anon-aromatic heterocyclic oxy group (the heterocyclic oxy group isoptionally substituted with 1 or 2 oxo group(s)), a C₁₋₆ alkyl group(the C₁₋₆ alkyl group is optionally substituted with 1 to 5 halogenatom(s), 1 to 5 —OH, or 1 to 5 C₁₋₄ alkoxy group(s)), a C₂₋₆ alkenylgroup, a C₂₋₇ alkanoyl group, an aralkyloxy group, a non-aromaticheterocyclic carbonyl group (the heterocyclic carbonyl group isoptionally substituted with 1 to 2 oxo group(s)), a —S(O)_(i)R^(a) (i isan integer of 0 to 2) group, a —CONR^(d)R^(e) group, and a—CONR^(d3)R^(e3) group (R^(d3) is a hydrogen atom or a C₁₋₄ alkyl group;and R^(e3) is a C₁₋₆ alkyl group (the C₁₋₆ alkyl group is substitutedwith 1 to 5 group(s) optionally selected from —OH, a C₁₋₆ alkoxy group,a non-aromatic heterocyclic group (the heterocyclic group is optionallysubstituted with 1 to 2 C₁₋₄ alkyl group(s) or 1 to 2 oxo group(s)), anda —S(O)_(i)R^(a) (i is an integer of 0 to 2) group))). Substitution withone to three substituent(s) RIIa is preferable.

More specific examples of Ls include the groups specifically exemplifiedabove as the “halogen atom”, the “C₁₋₆ alkyl group which is optionallysubstituted with 1 to 5 substituent(s) RI”, the “C₁₋₆ alkoxy group whichis optionally substituted with 1 to 5 substituent(s) RI”, the “arylgroup which is optionally substituted with 1 to 5 substituent(s) RII”,the “heterocyclic group which is optionally substituted with 1 to 5substituent(s) RII”, the “aralkyl group which is optionally substitutedwith 1 to 5 substituent(s) RII”, the “heteroarylalkyl group which isoptionally substituted with 1 to 5 substituent(s) RII”, the“non-aromatic heterocyclic alkyl group which is optionally substitutedwith 1 to 5 substituent(s) RII”, the “aryloxy group which is optionallysubstituted with 1 to 5 substituent(s) RII”, the “heteroaryloxy groupwhich is optionally substituted with 1 to 5 substituent(s) RII”, the“non-aromatic heterocyclic oxy group which is optionally substitutedwith 1 to 5 substituent(s) RII”, the “aralkyloxy group which isoptionally substituted with 1 to 5 substituent(s) RII”, the“heteroarylalkyloxy group which is optionally substituted with 1 to 5substituent(s) RII”, the substituted spiropiperidinylmethyl group”, andthe like.

[1-2] In the compound of Formula (I) according to Aspect [1], R¹s areindependently a group optionally selected from a halogen atom, a C₁₋₆alkyl group which is optionally substituted with 1 to 5 substituent(s)RI, a C₂₋₆ alkenyl group which is optionally substituted with 1 to 5substituent(s) RI, a C₂₋₆ alkynyl group which is optionally substitutedwith 1 to 5 substituent(s) RI, a C₁₋₆ alkoxy group which is optionallysubstituted with 1 to 5 substituent(s) RI (the substituents RI are thesame as or different from each other and are the same as defined as thesubstituent(s) RI above), and a cyano group.

[1-2-a] Preferable examples of R¹s include a halogen atom, a C₁₋₄ alkylgroup which is optionally substituted with 1 to 5 substituent(s) RI, aC₁₋₄ alkoxy group which is optionally substituted with 1 to 5substituent(s) RI (the substituents RI are the same as or different fromeach other and are the same as defined as the substituent(s) RI above),and a cyano group.

[1-2-b] More preferable examples of R¹s include a halogen atom, a C₁₋₄alkyl group which is optionally substituted with 1 to 5 halogen atom(s),a C₁₋₄ alkoxy group which is optionally substituted with 1 to 5 halogenatom(s), and a cyano group. Specific examples of R¹ include a fluorineatom, a chlorine atom, a bromine atom, methyl, ethyl, propyl, isopropyl,butyl, isobutyl, sec-butyl, tert-butyl, trifluoromethyl, methoxy,ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy,trifluoromethoxy, and cyano.

[1-3] In the compound of Formula (I) according to Aspect [1], R^(2a) andR^(2b) are independently a group optionally selected from a hydrogenatom, a halogen atom, a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, a C₂₋₆alkynyl group, a C₁₋₆ alkoxy group, and a cyano group.

[1-3-a] Preferable examples of R^(2a) and R^(2b) independently include ahydrogen atom, a halogen atom, and a C₁₋₄ alkyl group, and specificexamples thereof include a hydrogen atom, a fluorine atom, a chlorineatom, a bromine atom, and methyl.

[1-3-b] More preferably, any one of R^(2a) and R^(2b) is a hydrogenatom, and further preferably, both of R^(2a) and R^(2b) are a hydrogenatom.

[1-4] In the compound of Formula (I) according to Aspect [1], R³, R⁴,R⁵, R⁶, and R⁷ are independently a group optionally selected from ahydrogen atom, a C₁₋₆ alkyl group, a halogenated C₁₋₆ alkyl group, aC₂₋₆ alkenyl group, and a C₂₋₆ alkynyl group.

[1-4-a] R³, R⁴, R⁵, R⁶, and R⁷ are preferably a hydrogen atom.

[1-5] In the compound of Formula (I) according to Aspect [1], R^(11a)and R^(11b) are independently a group optionally selected from ahydrogen atom, a halogen atom, a C₁₋₆ alkyl group, a halogenated C₁₋₆alkyl group, a C₂₋₆ alkenyl group, a C₂₋₆ alkynyl group, a C₁₋₆ alkoxygroup, a halogenated C₁₋₆ alkoxy group, a C₂₋₇ alkanoyl group, and acarboxy group which is optionally protected.

[1-5-a] Preferable examples of R^(11a) and R^(11b) independently includea hydrogen atom, a halogen atom, a C₁₋₄ alkyl group, a halogenated C₁₋₄alkyl group, a C₂₋₅ alkanoyl group, and a carboxy group. Morespecifically, R^(11a) and R^(11b) are independently a hydrogen atom, afluorine atom, a chlorine atom, a bromine atom, methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, trifluoromethyl,acetyl, carboxy, or the like, more preferably a hydrogen atom.

[1-6] In the compound of Formula (I) according to Aspect [1], R^(12a)and R^(12b) are independently a group optionally selected from ahydrogen atom, a halogen atom, a C₁₋₆ alkyl group, a halogenated C₁₋₆alkyl group, a C₂₋₆ alkenyl group, a C₂₋₆ alkynyl group, a C₁₋₆ alkoxygroup, a halogenated C₁₋₆ alkoxy group, and a cyano group.

[1-6-a] Preferable examples of R^(12a) and R^(12b) independently includea hydrogen atom, a halogen atom, a C₁₋₄ alkyl group, a halogenated C₁₋₄alkyl group, and a cyano group. Specifically, R^(12a) and R^(12b) are ahydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, methyl,ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl,trifluoromethyl, cyano, or the like.

[1-6-b] More preferably, any one of R^(12a) and R^(12b) is a hydrogenatom, and further preferably, both of R^(12a) and R^(12b) are a hydrogenatom.

[1-7] In the compound of Formula (I) according to Aspect [1], R^(11c)and R^(12c) are independently a group optionally selected from ahydrogen atom, a C₁₋₆ alkyl group, and a halogenated C₁₋₆ alkyl group.

[1-7-a] Preferable examples of R^(11c) and R^(12c) independently includea hydrogen atom and a C₁₋₄ alkyl group. More specifically, R^(11c) andR^(12c) are independently a hydrogen atom, a fluorine atom, a chlorineatom, a bromine atom, methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, tert-butyl, or the like. More preferably, R^(11c) and R^(12c)are a hydrogen atom.

[1-8] In the compound of Formula (I) according to Aspect [1], X is anoxygen atom, a sulfur atom, or —NR⁷— (R⁷ is the same as defined as R⁷above).

[1-8-a] Preferably, X is an oxygen atom or —NH—.

[1-8-b] More preferably, X is an oxygen atom.

[1-9] In the compound of Formula (I) according to Aspect [1], j is aninteger of 0 to 3, while k is an integer of 0 to 2. Preferably, j is 0or 1, while k is 0. When the ring A is a monocyclic ring or a spiroring, more preferably, j is 1, while k is 0. When the ring A is a fusedring, more preferably, j is 0, while k is 0.

[1-10] In the compound of Formula (I) according to Aspect [1], the ringB is a C₆₋₁₄ aryl group or a 5- to 14-membered heteroaryl group,preferably a benzene ring, a pyridine ring, a pyrimidine ring, orFormula (BB1) or Formula (BB2):

(where p and R¹ are the same as defined in Formula (I); G is a carbonatom or a nitrogen atom; W₁ is a single bond, an oxygen atom, a sulfuratom, —CH₂—, —CF₂—, —CO—, —SO—, or —SO₂—; W₂ is a single bond or —CH₂—;W₃ is none or —CH₂—; and ● is a single bond with a cyclic amidestructure moiety). The ring B is more preferably a benzene ring, apyridine ring, Formula (BB1), or Formula (BB2), further preferably abenzene ring.

Preferable aspects of p and R¹ in Formula (BB1) and Formula (BB2) arethe same as the preferable aspects described in the below Aspect [1-11]and the above Aspects [1-2-a] to [1-2-b].

[1-10-a] In Formula (BB1) or Formula (BB2), G is preferably a carbonatom.

[1-10-b] In Formula (BB1), W₁ is preferably an oxygen atom, a sulfuratom, or —CH₂—. When W₃ is —CH₂—, W₂ is preferably —CH₂—.

[1-10-c] In Formula (BB2), W₁ is preferably a single bond, an oxygenatom, a sulfur atom, or —CH₂—. When W₃ is —CH₂—, W₂ is preferably —CH₂—.

[1-11] In the compound of Formula (I) according to Aspect [1], p is aninteger of 0 to 4. p is preferably 0 or 1.

[1-12] In the compound of Formula (I) according to Aspect [1], n is aninteger of 0 to 2; h is an integer of 0 to 3; J₁ is —CR^(11a)R^(11b)— or—NR^(11c)—; and J₂ is —CR^(12a)R^(12b)— or NR^(12c)— (with the provisothat when J₁ is —NR^(11c)—, h is 0). n is preferably 1 or 2. When J₁ is—CR^(11a)R^(11b)— and h is 0, n is more preferably 1. When J₁ is—NR^(11c)— and h is 0, n is more preferably 2. When h is an integer of 1to 3, n is more preferably 2.

[1-13] In the compound of Formula (I) according to Aspect [1], the ringA is a C₆₋₁₄ aryl group which is optionally substituted with 1 to 5L(s), a 3- to 14-membered heterocyclic group which is optionallysubstituted with 1 to 5 L(s), a C₅₋₇ cycloalkyl group which isoptionally substituted with 1 to 5 L(s), a C₅₋₇ cycloalkenyl group whichis optionally substituted with 1 to 5 L(s), a 6- to 14-membered spiroring group which is optionally substituted with 1 to 5 L(s), or a2-phenylamino-2-oxoacetyl group which is optionally substituted with 1to 5 L(s).

[1-13-a] Preferably, the ring A is phenyl which is optionallysubstituted with 1 to 5 L(s), a C₆₋₁₄ fused aryl group which isoptionally substituted with 1 to 5 L(s) and partly hydrogenated, a 5- to7-membered monocyclic heteroaryl group which is optionally substitutedwith 1 to 5 L(s), an 8- to 14-membered ring-fused heteroaryl group whichis optionally substituted with 1 to 5 L(s), an 8- to 14-memberedring-fused heteroaryl group which is optionally substituted with 1 to 5L(s) and partly hydrogenated, a 3- to 8-membered non-aromaticheterocyclic group which is optionally substituted with 1 to 5 L(s), aC₅₋₇ cycloalkenyl group which is optionally substituted with 1 to 5L(s), or a 7- to 13-membered spiro ring group which is optionallysubstituted with 1 to 5 L(s).

[1-13-b] More preferably, the ring A is phenyl which is optionallysubstituted with 1 to 5 L(s), indanyl which is optionally substitutedwith 1 to 5 L(s), 1,2,3,4-tetrahydronaphthyl which is optionallysubstituted with 1 to 5 L(s), thienyl which is optionally substitutedwith 1 to 5 L(s), thiazolyl which is optionally substituted with 1 to 5L(s), phthalazinyl which is optionally substituted with 1 to 5 L(s),1,2,3,4-tetrahydro-4-isoquinolyl which is optionally substituted with 1to 5 L(s), 1,2,3,4-tetrahydro-4-quinolyl which is optionally substitutedwith 1 to 5 L(s), dihydrobenzofuranyl which is optionally substitutedwith 1 to 5 L(s), chromanyl which is optionally substituted with 1 to 5L(s), pyrrolidinyl which is optionally substituted with 1 to 5 L(s),piperidinyl which is optionally substituted with 1 to 5 L(s), acyclohexenyl group which is optionally substituted with 1 to 5 L(s), ora 7- to 13-membered spiro ring group which is optionally substitutedwith 1 to 5 L(s).

[1-13-b-1] Further preferably, the ring A is phenyl which is optionallysubstituted with 1 to 5 L(s), thienyl which is optionally substitutedwith 1 to 5 L(s), thiazolyl which is optionally substituted with 1 to 5L(s), phthalazinyl which is optionally substituted with 1 to 5 L(s),1,2,3,4-tetrahydro-4-isoquinolyl which is optionally substituted with 1to 5 L(s), 1,2,3,4-tetrahydro-4-quinolyl which is optionally substitutedwith 1 to 5 L(s), pyrrolidinyl which is optionally substituted with 1 to5 L(s), piperidinyl which is optionally substituted with 1 to 5 L(s), acyclohexenyl group which is optionally substituted with 1 to 5 L(s), ora 7- to 13-membered spiro ring group which is optionally substitutedwith 1 to 5 L(s).

[1-13-b-2] Most preferably, the ring A is phenyl which is optionallysubstituted with 1 to 5 L(s), thienyl which is optionally substitutedwith 1 to 5 L(s), thiazolyl which is optionally substituted with 1 to 5L(s), pyrrolidinyl which is optionally substituted with 1 to 5 L(s),piperidinyl which is optionally substituted with 1 to 5 L(s), acyclohexenyl group which is optionally substituted with 1 to 5 L(s), ora 7- to 13-membered spiro ring group which is optionally substitutedwith 1 to 5 L(s).

[1-13-c] The ring A in Formula (I) according to Aspect [1] is preferablyphenyl which is optionally substituted with 1 to 5 L(s). More preferableexamples of the ring A include Partial Structural Formula (A):

(where q and r are independently an integer of 0 to 4; s is an integerof 0 to 2 (with the proviso that q+s is an integer of 0 to 5);

-   the ring A′ is an aryl group or a heteroaryl group;-   V is a single bond or an oxygen atom;

R⁸s are independently a group optionally selected from a C₁₋₆ alkoxygroup which is substituted with 1 to 5 substituent(s) M, a C₂₋₆alkenyloxy group which is substituted with 1 to 5 substituent(s) M, aC₂₋₆ alkynyloxy group which is substituted with 1 to 5 substituent(s) M,a —CONR^(d)R^(e1) group, an aralkyloxy group, a heterocyclic oxy group(the heterocyclic oxy group is optionally substituted with 1 to 3 C₁₋₆alkyl group(s) or 1 to 3 oxo group(s)), a heterocyclic group (theheterocyclic group is optionally substituted with 1 to 3 C₁₋₆ alkylgroup(s) or 1 to 3 oxo group(s)), and a heterocyclic carbonyl group (theheterocyclic carbonyl group is optionally substituted with 1 to 3 C₁₋₆alkyl group(s) or 1 to 3 oxo group(s));

the substituents M are independently a group optionally selected from ahalogen atom, —OH, a C₁₋₆ alkoxy group, an aryl group (the aryl group isoptionally substituted with 1 to 3 halogen atom(s)), a heterocyclicgroup (the heterocyclic group is optionally substituted with 1 to 3 —OH,1 to 3 C₁₋₆ alkyl group(s), or 1 to 3 oxo group(s)), a —S(O)_(i)R^(a) (iis an integer of 0 to 2) group, a —NR^(b1)R^(c1) group, a—SO₂NR^(d)R^(e) group, and a —CONR^(d)R^(e) group;

R⁹s and R¹⁰s are independently a group optionally selected from ahalogen atom, —OH, a cyano group, a C₁₋₆ alkyl group which is optionallysubstituted with 1 to 5 substituent(s) RI, a C₂₋₆ alkenyl group which isoptionally substituted with 1 to 5 substituent(s) RI, a C₂₋₆ alkynylgroup which is optionally substituted with 1 to 5 substituent(s) RI, aC₁₋₆ alkoxy group which is optionally substituted with 1 to 5substituent(s) RI, a C₂₋₇ alkanoyl group, —SH, a —S(O)_(i)R^(a) (i is aninteger of 0 to 2) group, a —NR^(b1)R^(c1) group, and a —CONR^(d)R^(e)group;

the figures of 1 to 6 or 1′ to 6′ indicate where the ring A′-V— or eachsubstituent is bonded; and

R^(a), R^(d), R^(e), R^(b1), R^(c1), and R^(e1) are the same as definedin Formula (I)).

In Formula (A), the binding positions of the ring A′-V— and R¹⁰s are anypositions at which they can be optionally bonded in the benzene ring,and the binding positions of R⁸s and R⁹s are any positions at which theycan be optionally bonded in the ring A′.

In Formula (A), preferably, the ring A′ is a benzene ring, a pyridinering, or a pyrimidine ring. Namely, preferable examples of Formula (A)include Formula (A)-1:

(where q, r, s, V, R⁸s, R⁹s, and R¹⁰s are the same as defined in Formula(A); and the ring A″ is a benzene ring, a pyridine ring, or a pyrimidinering).

[1-13-c-1] Preferable examples of Formula (A) include Formula (A1) orFormula (A2):

(where q, r, s, the ring A′, R⁸s, R⁹s, and R¹⁰s are the same as definedin Formula (A) described in Aspect [1-13-c]; and the broken lines andthe Figures 3 and 4 or the Figures 3′ and 4′ indicate where the ring A′,the ring A′-O—, or R⁸s are bonded).

Here, when the position of the single bond of the phenyl group (thebinding position with the linker moiety containing X) is determined as1-position, the binding position of the ring A′ in Formula (A1) is3-position or 4-position, preferably 3-position. In the case that thering A′ is a 6-membered ring, when the binding position with the phenylgroup of the ring A′ is determined as 1′-position, the binding positionof R⁸ in Formula (A1) is preferably 3′-position or 4′-position.

When the position of the single bond of the phenyl group (the bindingposition with the linker moiety containing X) is determined as1-position, the binding position of the ring A′-O— in Formula (A2) is3-position or 4-position, preferably 3-position. In the case that thering A′ is a 6-membered ring, when the binding position with the phenylgroup-O— of the ring A′ is determined as 1′-position, the bindingposition of R⁸ in Formula (A2) is preferably 3′-position or 4′-position.

In Formula (A1) or Formula (A2), preferably, the ring A′ is a benzenering, a pyridine ring, or a pyrimidine ring. Namely, preferable examplesof Formula (A1) or Formula (A2) include Formula (A1)-1 or Formula(A2)-1:

(where q, r, s, R⁸s, R⁹s, and R¹⁰s are the same as defined in Formula(A) described in Aspect [1-13-c]; the ring A″ is the same as defined inFormula (A)-1 described in Aspect [1-13-c]; and the broken lines and theFigures 3 and 4 or the Figures 3 ′ and 4 ′ indicate where the ring A″,the ring A″-O—, or R⁸s are bonded).

Here, when the position of the single bond of the phenyl group (thebinding position with the linker moiety containing X) is determined as1-position, the binding position of the ring A″ or the ring A″-O— inFormula (A1)-1 or Formula (A2)-1 is preferably 3-position. When thebinding position with the phenyl group or the phenyl group-O— of thering A″ is determined as 1′-position, the binding position of R⁸ inFormula (A1)-1 or Formula (A2)-1 is preferably 4′-position.

[1-13-c-1-1] More specifically, Formula (A) is preferably the abovePartial Structural Formula (A1) or Formula (A1)-1.

[1-13-c-2] In Formula (A), Formula (A1), or Formula (A2), morespecifically, the ring A′ is preferably benzene, naphthalene, pyridine,pyrimidine, thiophene, quinoline, benzimidazole, or dibenzofuran, morepreferably benzene, pyridine, pyrimidine, thiophene, or quinoline.Further preferably, the ring A′ is benzene, pyridine, or pyrimidine,that is, the ring A″ (Formula (A)-1, Formula (A1)-1, or Formula (A2)-1).Most preferably, the ring A′ and the ring A″ are benzene or pyridine.

[1-13-c-3] More specifically, Formula (A) is more preferably the abovePartial Structural Formula (A), Formula (A)-1, Formula (A1), Formula(A2), Formula (A1)-1, or Formula (A2)-1 in which s is 0 or 1. Inaddition, preferably, any one of q and s is 1 or more.

[1-13-c-3-1] More preferably, Formula (A) is Formula (A1a) or Formula(A1b) when s is 1 in Formula (A1)-1, and Formula (A) is Formula (A1c)when s is 0 in Formula (A1)-1:

(where q, r, R⁸, R⁹ and R¹⁰ are the same as defined in the above Formula(A) described in Aspect [1-13-c]; and G₁, G₂, G₃, and G₄ are a ═CH—group, a ═CR⁹— group, or a nitrogen atom (with the proviso that when G₁is a nitrogen atom, G₂ and G₃ are a ═CH— group or a ═CR⁹— group)).

In Formula (A1a), Formula (A1b), or Formula (A1c), when the position ofthe single bond of the phenyl group (the binding position with thelinker moiety containing X) is determined as 1-position, R¹⁰ can bebonded at 2-position, 4-position, 5-position, or 6-position. The bindingposition of R⁹ is any positions at which it can be optionally bonded inthe ring including G₁ or G₄.

Formula (A) is more preferably Formula (A1a) or Formula (A1c).

[1-13-c-3-2] In Formula (A1a), preferably, G₁ is a ═CH— group or a ═CR⁹—group; and G₂ and G₃ are independently a ═CH— group, a ═CR⁹— group, or anitrogen atom. More preferably, G₁ and G₃ are independently a ═CH— groupor a ═CR⁹— group; and G₂ is a═CH— group, a ═CR⁹— group, or a nitrogenatom.

In Formula (A1c), preferably, G₁ is a ═CH— group or a ═CR⁹— group; andG₂ and G₃ are independently a ═CH— group, a ═CR⁹— group or a nitrogenatom. More preferably, G₁ and G₃ are independently a ═CH— group or a═CR⁹— group; and G₂ is a ═CH— group, a ═CR⁹— group, or a nitrogen atom.

[1-13-c-4] More specifically, Formula (A) is preferably Formula (A),Formula (A)-1, Formula (A1), Formula (A2), Formula (A1)-1, Formula(A2)-1, Formula (A1a), Formula (A1b), or Formula (A1c) in which r is 0or 1. When r is not 0, at least one of the binding positions of R¹⁰ ispreferably 2-position, and when r is 1, the binding position of R¹⁰ ispreferably 2-position.

[1-13-c-5] More specifically, Formula (A) is preferably Formula (A),Formula (A)-1, Formula (A1), Formula (A2), Formula (A1)-1, Formula(A2)-1, Formula (A1a), Formula (A1b), or Formula (A1c) in which q is aninteger of 0 to 3, more preferably Formula (A), Formula (A)-1, Formula(A1), Formula (A2), Formula (A1)-1, Formula (A2)-1, Formula (A1a),Formula (A1b), or Formula (A1c) in which q is an integer of 1 to 3.Preferably, any one of q and s is 1 or more.

[1-13-c-5-1] In Formula (A1a), when the binding position of the ringcontaining G₁ with 3-position of the phenyl group is determined as1′-position, the binding position of R⁹ when q is 1 is preferably2′-position (with the proviso that the case where G₁ is a nitrogen atomis excluded) or 6′-position. The binding positions of R^(9s) when q is 2are preferably 2′-position and 6′-position, 2′-position and 5′-position,or 5′-position and 6′-position (with the proviso that the case where thebinding position is a nitrogen atom is excluded), and more preferably,2′-position and 6′-position or 2′-position and 5′-position. The bindingpositions of R⁹ when q is 3 are preferably 2′-position, 5′-position, and6′-position (with the proviso that the case where the binding positionis a nitrogen atom is excluded).

In Formula (A1c), when the binding position of the ring containing G₁with 3-position of the phenyl group is determined as 1′-position, thebinding position of R⁹ when q is 1 is preferably 2′-position (with theproviso that the case where G₁ is a nitrogen atom is excluded) or6′-position. The binding positions of R⁹s when q is 2 are preferably2′-position and 6′-position, 2′-position and 5′-position, 2′-positionand 4′-position, 4′-position and 6′-position, or 5′-position and6′-position (with the proviso that the case where the binding positionis a nitrogen atom is excluded), and more preferably, 2′-position and6′-position, 2′-position and 5′-position, or 2′-position and4′-position. The binding positions of R⁹s when q is 3 are preferably2′-position, 5′-position and 6′-position, or 2′-position, 4′-positionand 6′-position, or 2′-position, 4′-position and 5′-position (with theproviso that the case where the binding position is a nitrogen atom isexcluded).

[1-13-c-6] In Formula (A1a), r is preferably 0 or 1. When r is 1, thebinding position of R¹⁰ is preferably 2-position. When G₁ is a ═CH—group or a ═CR⁹— group, G₂ is a ═CH— group or a nitrogen atom, G₃ is a═CH— group, and q is 1 or 2, the binding position(s) of R⁹(s) is morepreferably 2′-position and/or 6′-position.

In Formula (A1c), r is preferably 0 or 1. When r is 1, the bindingposition of R¹⁰ is preferably 2-position. When G₁ is a ═CH— group or a═CR⁹— group, G₂ is a ═CH— group or a nitrogen atom, G₃ is a ═CH— group,and q is 1 or 2, the binding position(s) of R⁹(s) is more preferably2′-position and/or 6′-position.

[1-13-c-7] In Formula (A), Formula (A)-1, Formula (A1), Formula (A2),Formula (A1)-1, Formula (A2)-1, Formula (A1a), or Formula (A1b), R⁸s areindependently a C₁₋₆ alkoxy group which is substituted with 1 to 5substituent(s) Ma, a C₂₋₆ alkenyloxy group which is substituted with 1to 5 substituent(s) Ma, a C₂₋₆ alkynyloxy group which is substitutedwith 1 to 5 substituent(s) Ma, a —CONR^(d)R^(e2) group, an aralkyloxygroup, a non-aromatic heterocyclic oxy group (the heterocyclic oxy groupis optionally substituted with 1 to 2 oxo group(s)), or a non-aromaticheterocyclic carbonyl group (the heterocyclic carbonyl group isoptionally substituted with 1 to 2 oxo group(s)); the substituents Maare independently a halogen atom, —OH, a C₁₋₆ alkoxy group, anon-aromatic heterocyclic group (the heterocyclic group is optionallysubstituted with 1 to 3 —OH, 1 to 3 C₁₋₆ alkyl group(s), or 1 to 3 oxogroup(s)), a —S(O)_(i)R^(a) (i is an integer of 0 to 2) group, a—NR^(b1)R^(c1) group, a —SO₂NR^(d)R^(e) group, and a —CONR^(d)R^(e)group; and R^(e2) is a C₁₋₆ alkyl group (the C₁₋₆ alkyl group isoptionally substituted with 1 to 5 halogen atom(s), 1 to 5 —OH, 1 to 5C₁₋₆ alkoxy group(s), 1 to 5 non-aromatic heterocyclic group(s) (theheterocyclic group is optionally substituted with 1 to 3 —OH, 1 to 3C₁₋₆ alkyl group(s), or 1 to 3 oxo group(s)), 1 to 5 —S(O)_(i)R^(a) (iis an integer of 0 to 2) group(s), 1 to 5 —SO₂NR^(d)R^(e) group(s), 1 to5 —CONR^(d)R^(e) group(s), or 1 to 5 —NR^(b1)R^(c1) group(s)).

[1-13-c-7-1] More preferable examples of R⁸ include a C₁₋₆ alkoxy group(the alkoxy group is substituted with 1 to 5 group(s) optionallyselected from —OH, a C₁₋₆ alkoxy group, a non-aromatic heterocyclicgroup (the heterocyclic group is optionally substituted with 1 to 2 —OH,1 to 2 C₁₋₄ alkyl group(s), or 1 to 2 oxo group(s)), a —S(O)_(i)R^(a) (iis an integer of 0 to 2) group, a —NR^(b2)R^(c2) group, a—SO₂NR^(d)R^(e) group, and a —CONR^(d)R^(e) group), a —CONR^(d3)R^(e3)group, an aralkyloxy group, a non-aromatic heterocyclic oxy group (theheterocyclic oxy group is optionally substituted with 1 to 2 oxogroup(s)), and a non-aromatic heterocyclic carbonyl group (theheterocyclic carbonyl group is optionally substituted with 1 to 2 oxogroup(s)); R^(b2) and R^(c2) are independently a group optionallyselected from a hydrogen atom, a C₁₋₆ alkyl group, a C₂₋₇ alkanoyl group(the alkanoyl group is optionally substituted with —OH or a C₁₋₆ alkoxygroup), and a C₁₋₆ alkylsulfonyl group, where R^(b2) and R^(c2)optionally form, together with a nitrogen atom to which they are bonded,a 3- to 8-membered cyclic group, and in the cyclic group, one carbonatom is optionally substituted with a carbonyl group; and R^(d3) is ahydrogen atom or a C₁₋₄ alkyl group, and R^(e3) is a C₁₋₆ alkyl group(the C₁₋₆ alkyl group is substituted with 1 to 5 group(s) optionallyselected from —OH, a C₁₋₆ alkoxy group, a non-aromatic heterocyclicgroup (the heterocyclic group is optionally substituted with 1 to 2 —OH,1 to 2 C₁₋₄ alkyl group(s), or 1 to 2 oxo group(s)), and a—S(O)_(i)R^(a) (i is an integer of 0 to 2).

[1-13-c-7-2] Further preferable examples of R⁸ include a C₁₋₆ alkoxygroup (the alkoxy group is substituted with 1 to 5 —OH, 1 to 5 methoxy,1 to 5 ethoxy, 1 to 5 4-hydroxy-1,1-dioxidotetrahydro-2H-thiopyran-4-yl,1 to 5 3-methyloxetane-3-yl, 1 to 5 methylsulfonyl, 1 to 5ethylsulfonyl, 1 to 5—NH₂, 1 to 5 acetylamino, 1 to 5methylsulfonylamino, 1 to 5 2-oxo-1-pyrrolidinyl, 1 to 55-oxo-2-pyrrolidinyl, 1 to 5 sulfamoyl, 1 to 5 methylsulfamoyl, 1 to 5dimethylsulfamoyl, 1 to 5 carbamoyl, 1 to 5 methylcarbamoyl, or 1 to 5dimethylcarbamoyl), a —CONR^(d4)R^(e4) group (R^(d4) is a hydrogen atomor a C₁₋₄ alkyl group; and R^(e4) is a C₁₋₆ alkyl group (the C₁₋₆ alkylgroup is substituted with 1 to 5 —OH, 1 to 5 methoxy, 1 to 5 ethoxy, 1to 5 4-hydroxy-1,1-dioxidotetrahydro-2H-thiopyran-4-yl, 1 to 53-methyloxetane-3-yl, 1 to 5 methylsulfonyl, 1 to 5 ethylsulfonyl, 1 to5—NH₂, 1 to 5 acetylamino, 1 to 5 methylsulfonylamino, 1 to 52-oxo-1-pyrrolidinyl, 1 to 5 5-oxo-2-pyrrolidinyl, 1 to 5 sulfamoyl, 1to 5 methylsulfamoyl, 1 to 5 dimethylsulfamoyl, 1 to 5 carbamoyl, 1 to 5methylcarbamoyl, or 1 to 5 dimethylcarbamoyl), benzyloxy,(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxy, and(pyrrolidine-1-yl)carbonyl. The substitution number of —OH, methoxy,ethoxy, 4-hydroxy-1,1-dioxidotetrahydro-2H-thiopyran-4-yl,3-methyloxetane-3-yl, methylsulfonyl, ethylsulfonyl, —NH₂, acetylamino,methylsulfonylamino, 2-oxo-1-pyrrolidinyl, 5-oxo-2-pyrrolidinyl,sulfamoyl, methylsulfamoyl, dimethylsulfamoyl, carbamoyl,methylcarbamoyl, or dimethylcarbamoyl in the C₁₋₆ alkoxy group as R⁸ orthe C₁₋₆ alkyl group as R^(e4) is particularly preferably 1 to 2.

More specifically, R⁸ is 2-hydroxyethoxy, 3-hydroxypropoxy,3-hydroxybutoxy, 3-hydroxy-3-methylbutoxy, 2,3-dihydroxypropoxy,(2R)-2,3-dihydroxypropoxy, (2S)-2,3-dihydroxypropoxy,(3S)-3-hydroxybutoxy, (3R)-3-hydroxybutoxy,3-hydroxy-2-hydroxymethylpropoxy,3-hydroxy-2-hydroxymethyl-2-methylpropoxy, 2-ethoxyethoxy,(4-hydroxy-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy,(3-methyloxetane-3-yl)methoxy, 2-methylsulfonyl-ethoxy,3-methylsulfonyl-propoxy, 2-ethylsulfonyl-ethoxy,3-ethylsulfonyl-propoxy, 2-aminoethoxy, 3-aminopropoxy,2-acetylamino-ethoxy, 3-acetylamino-propoxy,2-methylsulfonylamino-ethoxy, 3-methylsulfonylamino-propoxy,2-(2-oxo-1-pyrrolidinyl)ethoxy, 3-(2-oxo-1-pyrrolidinyl)propoxy,(5-oxo-2-pyrrolidinyl)methoxy, 2-sulfamoyl-ethoxy, 3-sulfamoyl-propoxy,2-methylsulfamoyl-ethoxy, 3-methylsulfamoyl-propoxy,2-dimethylsulfamoyl-ethoxy, 3-dimethylsulfamoyl-propoxy,2-carbamoyl-ethoxy, 3-carbamoyl-propoxy, 2-methylcarbamoyl-ethoxy,3-methylcarbamoyl-propoxy, 2-dimethylcarbamoyl-ethoxy,3-dimethylcarbamoyl-propoxy, N-(2-hydroxyethyl)carbamoyl,N-(2-methoxyethyl)carbamoyl, N-(2-hydroxyethyl)-N-methylcarbamoyl,N-(2-methoxyethyl)-N-methylcarbamoyl,N-(2-methylsulfonyl-ethyl)carbamoyl,N-(2-methylsulfonyl-ethyl)-N-methylcarbamoyl,(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxy, benzyloxy,(pyrrolidine-1-yl)carbonyl, or the like.

The C₁₋₆ alkoxy group or the heterocyclic oxy group which aresubstituted with a group of A in Formula (I) or the like in WO2010/143733 pamphlet, particularly the C₁₋₆ alkoxy groups substitutedwith (2) to (8) which are shown in [9] (c) in p. 25 to 26 or theheterocyclic oxy group shown in [9] (e), and these groups shown inExamples can also be referred to as specific examples of R⁸ of thepresent specification. Similarly, formulae and the corresponding groupsshown in Examples in the pamphlets below can also be referred to asspecific examples of R⁸ of the present specification.

-   WO 2008/001931 pamphlet, a group of R¹—X—O— in Formula (I);-   WO 2010/123017 pamphlet, a group of R⁷ in Formula (I);-   WO 2010/123016 pamphlet, a group of R¹⁰ in Formula (I);-   WO 2009/054423 pamphlet, groups of A and B in Formula (II).

[1-13-c-8] In Formula (A), Formula (A)-1, Formula (A1), Formula (A2),Formula (A1)-1, Formula (A2)-1, Formula (A1a), Formula (A1b), or Formula(A1c), preferable examples of R⁹s independently include a halogen atom,a cyano group, a C₁₋₄ alkyl group (the C₁₋₄ alkyl group is optionallysubstituted with 1 to 5 halogen atom(s) or 1 to 5 —OH), a C₂₋₄ alkenylgroup, a C₁₋₄ alkoxy group (the C₁₋₄ alkoxy group is optionallysubstituted with 1 to 5 halogen atom(s)), a C₂₋₅ alkanoyl group, a—S(O)_(i)R^(a) (R^(a) is a C₁₋₄ alkyl group) group, a —CONR^(d)R^(e)(R^(d) and R^(e) are independently a hydrogen atom or a C₁₋₄ alkylgroup) group, and a —NR^(b1)R^(c1) group (R^(b1) and R^(c1) form,together with a nitrogen atom to which they are bonded, a 3- to8-membered cyclic group; and in the cyclic group, one or two carbonatom(s) is(are) optionally substituted with an atom optionally selectedfrom an oxygen atom, a sulfur atom, and a nitrogen atom or with acarbonyl group).

More preferably, R⁹s are independently a halogen atom, a cyano group, aC₁₋₄ alkyl group (the C₁₋₄ alkyl group is optionally substituted with 1to 5 halogen atom(s) or 1 to 5—OH), a C₂₋₃ alkenyl group, a C₁₋₄ alkoxygroup (the C₁₋₄ alkoxy group is optionally substituted with 1 to 5halogen atom(s)), a C₂₋₃ alkanoyl group, a —S(O)_(i)R^(a) (R^(a) is aC₁₋₂ alkyl group) group, a —CONR^(d)R^(e) (R^(d) and R^(e) areindependently a hydrogen atom or a C₁₋₂ alkyl group) group, or a—NR^(b1)R^(c1) group (R^(b1) and R^(c1) form, together with a nitrogenatom to which they are bonded, a 3- to 6-membered cyclic group; and inthe cyclic group, one or two carbon atom(s) is(are) optionallysubstituted with an oxygen atom, a nitrogen atom, or a carbonyl group).Further preferably, R⁹s are independently a halogen atom, a cyano group,a C₁₋₄ alkyl group which is optionally substituted with 1 to 5 halogenatom(s), or a C₁₋₄ alkoxy group which is optionally substituted with 1to 5 halogen atom(s).

More specific examples of R⁹ include a fluorine atom, a chlorine atom, abromine atom, cyano, methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, tert-butyl, trifluoromethyl, hydroxymethyl, 2-hydroxyethyl,methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy,tert-butoxy, cyclopropylmethoxy, trifluoromethoxy, trifluoroethoxy,vinyl, acetyl, methylsulfonyl, carbamoyl, methylcarbamoyl,dimethylcarbamoyl, 1-piperidinyl, 4-morpholinyl, and2-oxooxazolidin-3-yl. More preferable examples of R⁹ include a fluorineatom, cyano, methyl, ethyl, methoxy, and ethoxy.

The amino group, the C₁₋₆ alkylthio group, the C₁₋₆ alkyl group, theC₃₋₁₀ cycloalkyl group, or the C₁₋₆ alkoxy group which are substitutedwith a group of A in Formula (I) or the like in WO 2010/143733 pamphlet,particularly the C₁₋₆ alkyl group and the halogenated C₁₋₆ alkyl groupwhich are shown in [9] (b) in p. 25 to 26 or the C₁₋₆ alkoxy group whichis optionally substituted with (1) shown in [9] (c), and thecorresponding groups shown in Examples can also be referred to asspecific examples of R⁹ of the present specification. Similarly,formulae and the corresponding groups shown in Examples in the pamphletsbelow can also be referred to as specific examples of R⁹ of the presentspecification.

-   WO 2008/001931 pamphlet, groups of R², R³, R⁴, and R⁵ in Formula    (I);-   WO 2010/123017 pamphlet, groups of R⁵, R⁶, R⁷, and R^(Y) in Formula    (I);-   WO 2010/123016 pamphlet, groups of R⁸, R⁹, R¹⁰, and R^(Y) in Formula    (I);-   WO 2009/054423 pamphlet, groups of R³, R⁴, A, and B in Formula (II)    and Formula (III).

[1-13-c-9] In Formula (A), Formula (A)-1, Formula (A1), Formula (A2),Formula (A1)-1, Formula (A2)-1, Formula (A1a), Formula (A1b), or Formula(A1e), preferable examples of R¹⁰s independently include a halogen atom,a C₁₋₄ alkyl group which is optionally substituted with 1 to 5 halogenatom(s), and a C₁₋₄ alkoxy group which is optionally substituted with 1to 5 halogen atom(s). More specific examples of R¹⁰ include a fluorineatom, a chlorine atom, a bromine atom, methyl, ethyl, propyl, isopropyl,butyl, isobutyl, sec-butyl, tert-butyl, trifluoromethyl, methoxy,ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy,and trifluoromethoxy. More preferable examples of R¹⁰ include a fluorineatom, methyl, ethyl, methoxy, and ethoxy.

[1-13-c-10] The preferable aspects of q, s, the ring A′, R⁸, and R⁹ ofthe Partial Structural Formula (A′):

(where q, s, the ring A′, R⁸, and R⁹ are the same as defined in Formula(A) in Aspect [1-13-c]) in Formula (A), Formula (A1), and Formula (A2)are the same as the preferable aspects described in Aspects [1-13-c-2],[1-13-c-3], [1-13-c-5], [1-13-c-7], [1-13-c-7-1], [1-13-c-7-2], or[1-13-c-8]. Examples of the preferable aspect of Formula (A′) includethe same groups as the groups having an aryl group or a heteroaryl groupamong the preferable aspects of L described in Aspect [1-1-d]. Specificexamples of Formula (A′) include specific examples of the “aryl groupwhich is optionally substituted with 1 to 5 substituent(s) RII” or thesame groups as the groups having a heteroaryl group among specificexamples of the “heterocyclic group which is optionally substituted with1 to 5 substituent(s) RII” that are described in Aspect [1]. Morespecific examples of Formula (A′) include the same groups as the groupshaving benzene, naphthalene, pyridine, pyrimidine, thiophene, quinoline,benzimidazole, or dibenzofuran.

Specific examples of the ring A″ moiety having (R⁸)_(s) and (R⁹)_(q) inFormula (A)-1, Formula (A1)-1, and Formula (A2)-1 include the samegroups as the groups having a benzene ring, a pyridine ring, or apyrimidine ring among specific examples of the “aryl group which isoptionally substituted with 1 to 5 substituent(s) RII” and specificexamples of the “heterocyclic group which is optionally substituted with1 to 5 substituent(s) RII” that are described in Aspect [1].

Specific examples of the ring moiety having R⁸ and (R⁹)_(q) in Formula(A1a), Formula (A1b), and Formula (A1c) include the groups having abenzene ring, a pyridine ring, or a pyrimidine ring and having any groupof R⁸ at the p-position or the m-position or not having any group of R⁸among specific examples of the “aryl group which is optionallysubstituted with 1 to 5 substituent(s) RII” and specific examples of the“heterocyclic group which is optionally substituted with 1 to 5substituent(s) RII” that are described in Aspect [1]. For example inFormula (A1a), specific examples of the ring moiety having R⁸ and(R⁹)_(q) include a phenyl group having any group of R⁸ at 4-position(such as 4-(3-hydroxy-3-methylbutoxy)phenyl) and a 3-pyridinyl grouphaving any group of R⁸ at 6-position (such as6-(3-methylsulfonyl-propoxy)pyridin-3-yl) and further include also agroup having simultaneously any groups of R⁹ (such as4-(2-ethoxy-ethoxy)-2,6-dimethylphenyl and6-((1,1-dioxidetetrahydro-2H-thiopyran-4-yl)oxy)-2-methylpyridin-3-yl).

Specific examples of the ring A′ moiety having (R⁸)_(s) and (R⁹)_(q) ofthe present specification also include the groups of A in Formula (I) orthe like in WO 2010/143733 pamphlet and the groups of Q in Formula (V)in WO 2007/033002 pamphlet, particularly the groups having a cyclicgroup among the corresponding groups shown in Examples of thesepamphlets. Similarly, also the corresponding groups shown in formulaeand Examples in the pamphlets below can be referred to as the specificexamples of the ring A′ moiety having (R⁸)_(s) and (R⁹)_(q) of thepresent specification.

-   WO 2008/001931 pamphlet, phenyl groups having R¹—X—O—, R², R³, R⁴,    and R⁵ in Formula (I);-   WO 2010/123017 pamphlet, 6-membered cyclic groups having R⁵, R⁶, and    R⁷ in Formula (I);-   WO 2010/123016 pamphlet, 6-membered cyclic groups having R⁸, R⁹, and    R¹⁰ in Formula (I);-   WO 2009/054423 pamphlet, groups of Formula (II) and Formula (III).

That is, 4-(3-methylsulfonyl-propoxy)-2,6-dimethylphenyl,4((1,1-dioxidetetrahydro-2H-thiopyran-4-yl)oxy)-2,6-dimethylphenyl,2-(4-morpholino)-4,6-dimethylpyrimidin-5-yl,2-ethyl-6,7-difluoro-1H-benzimidazol-1-yl,2-ethoxy-6,7-difluoro-1H-benzimidazol-1-yl, and the like are mentioned.

[1-13-c-11] Preferable examples of the ring A in Formula (I), Formula(A), Formula (A)-1, Formula (A1), Formula (A1)-1, or Formula (A1c)include Formula (A1)-1-1:

(where W, Y, and Z are ═CH— or a nitrogen atom (with the proviso that 0or 1 of W, Y, and Z is a nitrogen atom, and when R^(9c) is a fluorineatom, Z is ═CH—);

-   R^(9c) is a hydrogen atom, a fluorine atom, a chlorine atom, a    trifluoromethyl group, or a C₁₋₆ alkoxy group; R^(9d) is a hydrogen    atom, a fluorine atom, a chlorine atom, —OH, a C₁₋₄ alkyl group, a    C₁₋₃ alkoxy group, or a C₁₋₂ alkylthio group;-   R^(10a) is a C₁₋₁₀ alkyl group (the C₁₋₁₀ alkyl group is optionally    substituted with 1 to 4 halogen atom(s), 1 to 4 —OH, or 1 to 4 C₁₋₄    alkoxy group (the C₁₋₄ alkoxy group is optionally substituted with 1    to 4 halogen atom(s), 1 to 4 —OH, or 1 to 4 C₁₋₂ alkoxy group)), a    C₂₋₁₀ alkenyl group (the C₂₋₁₀ alkenyl group is optionally    substituted with 1 to 4 halogen atom(s), 1 to 4 —OH, or 1 to 4 C₁₋₄    alkoxy group(s) (the C₁₋₄ alkoxy group is optionally substituted    with 1 to 4 halogen atom(s), 1 to 4 —OH, or 1 to 4 C₁₋₂ alkoxy    group(s))), a C₁₋₁₀ alkoxy group (the C₁₋₁₀ alkoxy group is    optionally substituted with 1 to 4 halogen atom(s), 1 to 4 —OH, or 1    to 4 C₁₋₂ alkoxy group(s)), or a C₂₋₁₀ alkenyloxy group (the C₂₋₁₀    alkenyloxy group is optionally substituted with 1 to 4 halogen    atom(s), 1 to 4 —OH, or 1 to 4 C₁₋₂ alkoxy group(s)); and-   R^(10b), R^(10c), and R^(10d) are independently a hydrogen atom, a    fluorine atom, a chlorine atom, a C₁₋₄ alkyl group, or a C₁₋₄ alkoxy    group).

In Formula (A1)-1-1, preferable examples of R^(10a) include Formula(R^(10a′)):

(where R^(10a1), R^(10a2), and R^(10a3) are independently a hydrogenatom, a fluorine atom, or a C₁₋₄ alkyl group; at least two of, R^(10a1),R^(10a2), and R^(10a3) are other than a hydrogen atom; and R^(10a1),R^(10a2), and R^(10a3) optionally form, together with a carbon atom towhich they are bonded, a 3- to 8-membered cyclic group). Preferably, allof R^(10a1), R^(10a2), and R^(10a3) are a methyl group, or R^(10a1),R^(10a2), and R^(10a3) form a cyclopropyl group.

In Formula (A1)-1-1, W, Y, and Z are preferably ═CH—, R^(9c) ispreferably a fluorine atom or a butoxy group, R^(9d) is preferably amethoxy group, and R^(10b), R^(10c), and R^(10d) are preferably ahydrogen atom.

Specific examples of Formula (A1)-1-1 include6-(1,1-dimethylethyl)-2′-fluoro-5′-methoxy-1,1′-biphenyl-3-yl and2′-butoxy-6-(1,1-dimethylethyl)-5′-methoxy-1,1′-biphenyl-3-yl.

[1-13-c-12] Preferable examples of the ring A in Formula (I), Formula(A), Formula (A)-1, Formula (A1), or Formula (A1)-1 include Formula(A1)-1-2:

(where W, Y, Z, R^(9c), R^(9d), R^(10a), R^(10b), R^(10c), and R^(10d)are the same as defined in Formula (A1)-1-1 described in Aspect[1-13-c-11]).

In Formula (A1)-1-2, an alkyl chain or an alkenyl chain of R^(10a) is alinear, branched, or cyclic chain and also includes a linear chain orbranched chain group substituted with a cyclic group and a cyclic groupsubstituted with a linear chain or branched chain group. When R^(10a) isa C₁₋₁₀ alkyl group, specific examples of R^(10a) include Formula(R^(10a1)) described in Aspect [1-13-c-11]. More specific examples ofR^(10a) include 1,1-dimethylethyl(tert-butyl), 2,2-dimethylcyclopentyl,5,5-dimethylcyclopent-1-enyl, 2,2-dimethyl-1-hydroxypropyl, and2,2-dimethyl-1-methoxypropyl. Specific examples of R^(10a) of thepresent specification also include a group of A in Formula I in WO2009/048527 pamphlet, a group of A in Formula I and Formula III in WO2009/111056 pamphlet, and a group of A in Formula I′A in WO 2010/045258pamphlet, particularly the corresponding groups shown in Examples.

In Formula (A1)-1-2, W and Z are preferably ═CH—, R^(9c) is preferably afluorine atom, R^(9d) is preferably a methoxy group, R^(10b) and R^(10d)are preferably a hydrogen atom, and R^(10c) is preferably a hydrogenatom or a fluorine atom.

Specific examples of Formula (A1)-1-2 include2-(1,1-dimethylethyl)-2′-fluoro-5′-methoxy-1,1′-biphenyl-4-yl,2-(2,2-dimethylcyclopentyl)-2′-fluoro-5′-methoxy-1,1′-biphenyl-4-yl, and2-(2,2-dimethyl-1-methoxypropyl)-2′-fluoro-5′-methoxy-1,1′-biphenyl-4-yl.

[1-13-d] The ring A in Formula (I) according to Aspect [I] is preferablyPartial Structural Formula (AA):

(where f is an integer of 0 to 2; g is an integer of 1 to 4; q1 is aninteger of 0 to 3; q2 is 0 or 1; r1 is an integer of 0 to 2 (with theproviso that q1+q2+r1 is an integer of 0 to 5); the ring A′″ is abenzene ring or a pyridine ring;

-   T is —CH₂—, an oxygen atom, —S(O)_(i)— (i is an integer of 0 to 2),    or —NR⁷— (R⁷ is the same as R⁷ defined in Formula (I));-   R¹³s are independently a group optionally selected from a halogen    atom, —OH, a cyano group, a C₁₋₁₀ alkyl group which is optionally    substituted with 1 to 5 substituent(s) RI, a C₂₋₁₀ alkenyl group    which is optionally substituted with 1 to 5 substituent(s) RI, a    C₂₋₁₀ alkynyl group which is optionally substituted with 1 to 5    substituent(s) RI, a C₁₋₁₀ alkoxy group which is optionally    substituted with 1 to 5 substituent(s) RI, a C₂₋₁₀ alkenyloxy group    which is optionally substituted with 1 to 5 substituent(s) RI, a    C₂₋₁₀ alkynyloxy group which is optionally substituted with 1 to 5    substituent(s) RI, —SH, a —S(O)_(i)R^(a) (i is an integer of 0 to 2)    group, and a —NR^(b)R^(c) group;-   R^(13a) is a group optionally selected from an aryl group which is    optionally substituted with 1 to 5 substituent(s) RII, a    heterocyclic group which is optionally substituted with 1 to 5    substituent(s) RII, an aralkyl group which is optionally substituted    with 1 to 5 substituent(s) RII, a heteroarylalkyl group which is    optionally substituted with 1 to 5 substituent(s) RII, a    non-aromatic heterocyclic alkyl group which is optionally    substituted with 1 to 5 substituent(s) RII, an aryloxy group which    is optionally substituted with 1 to 5 substituent(s) RII, a    heteroaryloxy group which is optionally substituted with 1 to 5    substituent(s) RII, a non-aromatic heterocyclic oxy group which is    optionally substituted with 1 to 5 substituent(s) RII, an aralkyloxy    group which is optionally substituted with 1 to 5 substituent(s)    RII, a heteroarylalkyloxy group which is optionally substituted with    1 to 5 substituent(s) RII, and a substituted spiropiperidinylmethyl    group;-   R¹⁴s are independently a group optionally selected from a halogen    atom, —OH, a cyano group, a C₁₋₆ alkyl group which is optionally    substituted with 1 to 5 substituent(s) RI, a C₂₋₆ alkenyl group    which is optionally substituted with 1 to 5 substituent(s) RI, a    C₂₋₆ alkynyl group which is optionally substituted with 1 to 5    substituent(s) RI, a C₁₋₆ alkoxy group which is optionally    substituted with 1 to 5 substituent(s) RI, —SH, a —S(O)_(i)R^(a) (i    is an integer of 0 to 2) group, and a —NR^(b)R^(c) group; and-   R^(a), R^(b), R^(c), the substituent RI, and the substituent RII are    the same as defined in Formula (I)). In Formula (AA), the binding    positions of the linker moiety containing X and R¹⁴s are any    positions at which they can be optionally bonded in the ring    containing T, and the binding positions of R¹³ and R^(13a) are any    positions at which they can be optionally bonded in the ring A′″.

[1-13-d-1] Specific examples of Formula (AA) include Formula (AA)-1:

(where f, g, q1, r1, the ring A′″, T, R¹³, and R¹⁴ are the same asdefined in Formula (AA) described in Aspect [1-13-d]; and q, s, the ringA′, V, R⁸, and R⁹ are the same as defined in Formula (A) described inAspect [1-13-c]). In Formula (AA)-1, the binding positions of the linkermoiety containing X and R¹⁴s are any positions at which they can beoptionally bonded in the ring containing T; the binding positions of thering A′-V— and R¹³ are any positions at which they can be optionallybonded in the ring A′″; and the binding positions of R⁸ and R⁹ are anypositions at which they can be optionally bonded in the ring A′.

The Formula (AA)-1 is preferably a Formula (AA)-1 in which the ring A′is a benzene ring, a pyridine ring, or a pyrimidine ring. That is,preferable examples of Formula (AA)-1 include Formula (AA)-1-1:

(where f, g, q1, r1, the ring A′″, T, R¹³, and R¹⁴ are the same asdefined in Formula (AA) described in Aspect [1-13-d]; q, s, V, R⁸, andR⁹ are the same as defined in Formula (A) described in Aspect [1-13-c];and the ring A″ is the same as defined in Formula (A)-1 described inAspect [1-13-c]).

[1-13-d-2] In Formula (AA), Formula (AA)-1, or Formula (AA)-1-1, thering A′″ is preferably a benzene ring.

[1-13-d-3] In Formula (AA), Formula (AA)-1, or Formula (AA)-1-1, f ispreferably 0 or 1, more preferably 0. g is preferably 2 or 3, morepreferably 2. Preferably, f is 0 and g is 2 or 3, and more preferably, fis 0 and g is 2.

[1-13-d-4] Specific examples of Formula (AA) include Formula (AA1):

(where q1, q2, r1, T, R¹³, R^(13a), and R¹⁴ are the same as defined inFormula (AA) described in Aspect [1-13-d]; and the Figures 1 to 7indicate the binding position of a substituent in the ring).

[1-13-d-4-1] In Formula (AA1), when the binding position of the linkermoiety containing X is determined as 1-position, the substitutionposition of R^(13a) is preferably 4-position or 5-position, morepreferably 4-position.

[1-13-d-5] More specifically, Formula (AA), Formula (AA)-1, Formula(AA)-1-1, or Formula (AA1) is preferably Formula (AA1)-1:

(where q1, r1, T, R¹³, and R¹⁴ are the same as defined in Formula (AA)described in Aspect [1-13-d]; and q, s, the ring A′, V, R⁸, and R⁹ arethe same as defined in Formula (A) described in Aspect [1-13-c]).

[1-13-d-5-1] Specific examples of Formula (AA1)-1 include Formula(AA1a)-1:

(where q1, r1, R¹³, and R¹⁴ are the same as defined in Formula (AA)described in Aspect [1-13-d]; and q, s, the ring A′, V, R⁸, and R⁹ arethe same as defined in Formula (A) described in Aspect [1-13-c]).

The Formula (AA1a)-1 is preferably a Formula (AA1a)-1 in which the ringA′ is a benzene ring, a pyridine ring, or a pyrimidine ring. That is,preferable examples of Formula (AA1a)-1 include Formula (AA1a)-1-1:

(where q1, r1, R¹³, and R¹⁴ are the same as defined in Formula (AA)described in Aspect [1-13-d]; q, s, V, R⁸, and R⁹ are the same asdefined in Formula (A) described in Aspect [1-13-c]; and the ring A″ isthe same as defined in Formula (A)-1 described in Aspect [1-13-c]).

[1-13-d-6] In Formula (AA), Formula (AA)-1, Formula (AA)-1-1, Formula(AA1), or Formula (AA1)-1, T is preferably —CH₂— or an oxygen atom.

[1-13-d-7] More specific examples of Formula (AA) or Formula (AA 1)include Formula (AA1b):

(where q1, q2, r1, R¹³, R^(13a), and R¹⁴ are the same as defined inFormula (AA) described in Aspect [1-13-d]; and the Figures 1 to 7indicate the binding position of a substituent in the ring).

[1-13-d-7-1] More specific examples of Formula (AA1)-1 or Formula (AA1b)include Formula (AA1b)-1:

(where q1, r1, R¹³, and R¹⁴ are the same as defined in Formula (AA)described in Aspect [1-13-d]; and q, s, the ring A′, V, R⁸, and R⁹ arethe same as defined in Formula (A) described in Aspect [1-13-c]).

[1-13-d-8] In Formula (AA), Formula (AA)-1, Formula (AA)-1-1, Formula(AA1), Formula (AA1)-1, Formula (AA1a)-1, Formula (AA1a)-1-1, Formula(AA1b), or Formula (AA1b)-1, q1 is preferably 0 or 1, more preferably 0.

[1-13-d-9] In Formula (AA), Formula (AA1), or Formula (AA1b), q2 ispreferably 1.

[1-13-d-10] In Formula (AA), Formula (AA)-1, Formula (AA)-1-1, Formula(AA1), Formula (AA1)-1, Formula (AA1a)-1, Formula (AA1a)-1-1, Formula(AA1b), or Formula (AA1b)-1, r1 is preferably 0 or 1, more preferably 0.

[1-13-d-11] In Formula (AA), Formula (AA1), or Formula (AA1b),preferable examples of R^(13a) include a group optionally selected froman aryl group which is optionally substituted with 1 to 5 substituent(s)RII, a heterocyclic group which is optionally substituted with 1 to 5substituent(s) RII, an aralkyl group which is optionally substitutedwith 1 to 5 substituent(s) RII, a non-aromatic heterocyclic alkyl groupwhich is optionally substituted with 1 to 5 substituent(s) RII, anaryloxy group which is optionally substituted with 1 to 5 substituent(s)RII, a heteroaryloxy group which is optionally substituted with 1 to 5substituent(s) RII, a non-aromatic heterocyclic oxy group which isoptionally substituted with 1 to 5 substituent(s) RII, an aralkyloxygroup which is optionally substituted with 1 to 5 substituent(s) RII,and a substituted spiropiperidinylmethyl group (the substituent RII isthe same as defined in Aspect [1]).

[1-13-d-11-1] In Formula (AA), Formula (AA1), or Formula (AA1b), morepreferable examples of R^(13a) include a group optionally selected froman aryl group which is optionally substituted with 1 to 5 substituent(s)R^(11a), a heterocyclic group which is optionally substituted with 1 to5 substituent(s) R^(11a), an aralkyl group which is optionallysubstituted with 1 to 5 substituent(s) RIIa, a non-aromatic heterocyclicalkyl group which is optionally substituted with 1 to 5 substituent(s)RIIa, an aryloxy group which is optionally substituted with 1 to 5substituent(s) RIIa, a heteroaryloxy group which is optionallysubstituted with 1 to 5 substituent(s) RIIa, a non-aromatic heterocyclicoxy group which is optionally substituted with 1 to 5 substituent(s)RIM, an aralkyloxy group which is optionally substituted with 1 to 5substituent(s) RIIa, and a substituted spiropiperidinylmethyl group (thesubstituent RIM is the same as defined in Aspect [1-1-d]). The number ofsubstitutions by the substituent RIIa is preferably 1 to 3.

[1-13-d-11-2] In Formula (AA), Formula (AA1), or Formula (AA1b), morespecific examples of R^(13a) include the groups specifically exemplifiedas the “aryl group which is optionally substituted with 1 to 5substituent(s) RII”, the “heterocyclic group which is optionallysubstituted with 1 to 5 substituent(s) RII”, the “aralkyl group which isoptionally substituted with 1 to 5 substituent(s) RII”, the“heteroarylalkyl group which is optionally substituted with 1 to 5substituent(s) RII”, the “non-aromatic heterocyclic alkyl group which isoptionally substituted with 1 to 5 substituent(s) RII”, the “aryloxygroup which is optionally substituted with 1 to 5 substituent(s) RII”,the “heteroaryloxy group which is optionally substituted with 1 to 5substituent(s) RII”, the “non-aromatic heterocyclic oxy group which isoptionally substituted with 1 to 5 substituent(s) RII”, the “aralkyloxygroup which is optionally substituted with 1 to 5 substituent(s) RII”,the “heteroarylalkyloxy group which is optionally substituted with 1 to5 substituent(s) RII”, the “substituted spiropiperidinylmethyl group”,and the like.

Specific examples of R^(13a) of the present specification also includethe groups of A in Formula (II) in WO 2010/143733 pamphlet and thegroups of Q in Formula (V) in WO 2007/033002 pamphlet, particularly thegroups having a cyclic group among the corresponding groups shown inExamples of these pamphlets.

[1-13-d-11-3] Specific examples of R^(13a) include, in addition to thePartial Structural Formula (A′) described in Aspect [1-13-c-10], a groupin which Formula (A′) is substituted with an oxygen atom, a C₁₋₆ alkylgroup, or a C₁₋₆ alkoxy group. Particularly, when R^(13a) is a group ofFormula (A′) or a group in which Formula (A′) is substituted with anoxygen atom (Formula (A′)—O—), R^(13a) can be Formula (A′)-V—. Forexample, a Formula (AA) in which R^(13a) is Formula (A′) can be aFormula (AA)-1 in which V is a single bond. A Formula (AA) in whichR^(13a) is Formula (A′)—O— can be a Formula (AA)-1 in which V is anoxygen atom.

In Formula (AA)-1, Formula (AA1)-1, Formula (AA1a)-1, or Formula(AA1b)-1, more specific examples of the Formula (A′)-V-moiety when V isa single bond include the specific groups of the Partial StructuralFormula (A′) described in Aspect [1-13-c-10], that is, the same groupsas specific examples of the “aryl group which is optionally substitutedwith 1 to 5 substituent(s) RII”, or the groups having a heteroaryl groupamong specific examples of the “heterocyclic group which is optionallysubstituted with 1 to 5 substituent(s) RII” that are described in Aspect[1]. More specific examples of the Formula (A′)-V— moiety when V is anoxygen atom include the groups in which the specific groups of thePartial Structural Formula (A′) described in Aspect [1-13-c-10] aresubstituted with an oxygen atom, that is, the groups in which the samegroups as specific examples of the “aryl group which is optionallysubstituted with 1 to 5 substituent(s) RII”, or the groups having aheteroaryl group among specific examples of the “heterocyclic groupwhich is optionally substituted with 1 to 5 substituent(s) RII”, aresubstituted with an oxygen atom.

[1-13-d-12] In Formula (AA), Formula (AA)-1, Formula (AA)-1-1, Formula(AA1), Formula (AA1)-1, Formula (AA1a)-1, Formula (AA1a)-1-1, Formula(AA1b), or Formula (AA1b)-1, preferable examples of R¹³ include a groupoptionally selected from a halogen atom, a cyano group, a C₁₋₆ alkylgroup which is optionally substituted with 1 to 5 substituent(s) RI, aC₂₋₆ alkenyl group which is optionally substituted with 1 to 5substituent(s) RI, a C₂₋₆ alkynyl group which is optionally substitutedwith 1 to 5 substituent(s) RI, a C₁₋₆ alkoxy group which is optionallysubstituted with 1 to 5 substituent(s) RI, a C₂₋₆ alkenyloxy group whichis optionally substituted with 1 to 5 substituent(s) RI, a C₂₋₆alkynyloxy group which is optionally substituted with 1 to 5substituent(s) RI, and a —NR^(b)R^(c) group (the substituent RI is thesame as defined in Aspect [1]).

[1-13-d-12-1] In Formula (AA), Formula (AA)-1, Formula (AA)-1-1, Formula(AA1), Formula (AA1)-1, Formula (AA1a)-1, Formula (AA1a)-1-1, Formula(AA1b), or Formula (AA1b)-1, more preferable examples of R¹³ include agroup optionally selected from a halogen atom, a cyano group, a C₁₋₆alkyl group (the C₁₋₆ alkyl group is optionally substituted with 1 to 5halogen atom(s), 1 to 5 —OH, or 1 to 5 C₁₋₄ alkoxy group(s)), a C₂₋₆alkenyl group (the C₂₋₆ alkenyl group is optionally substituted with 1to 5 halogen atom(s), 1 to 5 —OH, or 1 to 5 C₁₋₄ alkoxy group(s)), aC₁₋₆ alkoxy group (the C₁₋₆ alkoxy group is optionally substituted with1 to 5 halogen atom(s), 1 to 5 —OH, or 1 to 5 C₁₋₄ alkoxy group(s)), anda C₂₋₆ alkenyloxy group (the C₂₋₆ alkenyloxy group is optionallysubstituted with 1 to 5 halogen atom(s), 1 to 5 —OH, or 1 to 5 C₁₋₄alkoxy group(s)).

[1-13-d-12-2] In Formula (AA), Formula (AA)-1, Formula (AA)-1-1, Formula(AA1), Formula (AA1)-1, Formula (AA1a)-1, Formula (AA1a)-1-1, Formula(AA1b), or Formula (AA1b)-1, specific examples of R¹³ include the groupsspecifically exemplified as the cyano group, the “halogen atom”, the“C₁₋₆ alkyl group which is optionally substituted with 1 to 5substituent(s) RI”, the “C₁₋₆ alkoxy group which is optionallysubstituted with 1 to 5 substituent(s) RI”, and the like. More specificexamples of R¹³ include a fluorine atom, a chlorine atom, a bromineatom, cyano, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, andtrifluoromethoxy.

[1-13-d-13] In Formula (AA), Formula (AA)-1, Formula (AA)-1-1, Formula(AA1), Formula (AA1)-1, Formula (AA1a)-1, Formula (AA1a)-1-1, Formula(AA1b), or Formula (AA1b)-1, preferable examples of R¹⁴ include ahalogen atom and a C₁₋₄ alkyl group which is optionally substituted with1 to 5 halogen atom(s). More specific examples of R¹⁴ include a fluorineatom, a chlorine atom, a bromine atom, methyl, ethyl, propyl, isopropyl,butyl, isobutyl, sec-butyl, tert-butyl, and trifluoromethyl.

[1-13-d-14] In Formula (AA)-1, Formula (AA)-1-1, Formula (AA1)-1,Formula (AA1a)-1, Formula (AA1a)-1-1, or Formula (AA1b)-1, preferableaspects of the ring A′, the ring A″, R⁸, and R⁹ are the same as thepreferable aspects described in Aspects [1-13-c-2], [1-13-c-7],[1-13-c-7-1] [1-13-c-7-2], or [1-13-c-8]. The ring A′ moiety having(R⁸)_(s), and (R⁹)_(q) can be Formula (N) described in Aspect[1-13-c-10] and the preferable aspects of the ring A′ moiety having(R⁸)_(s), and (R⁹)_(q) are the same as the preferable aspects describedin Aspect [1-13-c-10].

[1-13-d-15] In Formula (AA)-1, Formula (AA)-1-1, Formula (AA1)-1,Formula (AA1a)-1, Formula (AA1a)-1-1, or Formula (AA1b)-1, s ispreferably 0 or 1. q is preferably an integer of 0 to 3, more preferablyan integer of 0 to 2, further preferably 1 or 2. Preferably, any one ofq and s is 1 or more.

[1-13-d-15-1] In Formula (AA)-1, Formula (AA)-1-1, Formula (AA1)-1,Formula (AA1a)-1, Formula (AA1a)-1-1, or Formula (AA1b)-1, when s is 1,the binding position of R⁸ in the ring A′ is preferably the m-positionor the p-position, more preferably the p-position, relative to thebinding position of V.

[1-13-e] Preferable examples of the ring A in Formula (I) include thePartial Structural Formula (A)-IV:

(where q, r, s, the ring A′, R⁸, R⁹, and R¹⁰ are the same as defined inFormula (A) described in Aspect [1-13-c]; and the ring A1 is a 5- or6-membered heterocyclic group). In Formula (A)-IV, the binding positionsof R^(10s) are any positions at which they can be optionally bonded inthe ring A1, and the binding positions of R⁸s and R^(9a) are anypositions at which they can be optionally bonded in the ring A′.

[1-13-e-1] In Formula (A)-IV, the ring A1 is a 5- or 6-memberednon-aromatic heterocyclic group or a 5- or 6-membered heteroaryl group,and specifically, the ring A1 is preferably pyrrolidine, piperidine,furan, thiophene, imidazole, oxazole, thiazole, pyrazole, isoxazole,1,2,3-triazole, or 1,2,4-oxadiazole. More preferably, the ring A1 ispyrrolidine, piperidine, furan, thiophene, oxazole, or thiazole, furtherpreferably pyrrolidine, piperidine, thiophene, or thiazole.

[1-13-e-2] The ring A in Formula (I), or Formula (A)-IV is preferablythe Partial Structural Formula (A1)-IV:

(where q, r, s, the ring A′, R⁸, R⁹, and R¹⁰ are the same as defined inFormula (A) described in Aspect [1-13-c]; and g1 is 1 or 2). In Formula(A1)-IV, the binding positions of R¹⁰s are any positions at which theycan be optionally bonded in the pyrrolidine or piperidine ring, and thebinding positions of R⁸s and R⁹s are any positions at which they can beoptionally bonded in the ring A′.

[1-13-e-3] Preferable examples of the ring A in Formula (I), or Formula(A)-IV include the Partial Structural Formula (A2)-IV:

(where q, s, the ring A′, R⁸, and R⁹ are the same as defined in Formula(A) described in Aspect [1-13-c]; Z₁ is —CR^(10e)— or a nitrogen atom;Z₂ is a sulfur atom or an oxygen atom; Z₃ is —CR^(10f)- or a nitrogenatom; R^(10e) and R^(10f) are independently a hydrogen atom, a C₁₋₆alkyl group, or a methoxy group (with the proviso that at least one ofZ₁ and Z₃ is —CR^(10e)— or —CR^(10f)—)). In Formula (A2)-IV, the bindingpositions of R⁸s and R⁹s are any positions at which they can beoptionally bonded in the ring A′. Here, in Formula (A2)-IV, the ring A′may be a substituted spiropiperidinylmethyl group in addition to theabove description.

Specific examples of Formula (A2)-IV include Formula (A3)-IV describedin Aspect [1-13-e-7] below and Formula (A4)-IV described in Aspect[1-13-e-8] below. Specific examples of Formula (A2)-IV of the presentspecification also include groups corresponding to Formula (A2)-IV ofthe present specification in WO 2005/086661 pamphlet, WO 2005/051890pamphlet, WO 2004/022551 pamphlet, and WO 2004/011446 pamphlet (such asa 5-membered ring group and the like as examples of W in [0195] in p. 25of WO 2005/086661 pamphlet), particularly the corresponding groups shownin Examples of these pamphlets.

[1-13-e-4] In Formula (A)-IV, Formula (A1)-IV, or Formula (A2)-IV, morespecifically, the ring A′ is preferably benzene, pyridine, orpyrimidine. More preferably, the ring A′ is benzene or pyridine, furtherpreferably benzene.

[1-13-e-5] In Formula (A)-IV, Formula (A1)-IV, or Formula (A2)-IV, morespecifically, s is preferably 0 or 1, and when s is 1 and the ring A′ isa 6-membered ring, the substitution position of R⁸ is preferablyp-position. q is more preferably an integer of 0 to 2, furtherpreferably 1 or 2. Most preferably, s is 0 or 1 and q is 2.

[1-13-e-6] In Formula (A)-IV or Formula (A1)-IV, more specifically, r ispreferably 0.

[1-13-e-7] The ring A in Formula (I), Formula (A)-IV, or Formula (A2)-IVis preferably the Partial Structural Formula (A3)-IV:

(where q and R⁹ are the same as defined in Formula (A) described inAspect [1-13-c]; and R^(10f) is the same as defined in Formula (A2)-IVdescribed in Aspect [1-13-e-3]).

In Formula (A3)-IV, preferably, R⁹ is a group optionally selected from ahalogen atom, a cyano group, a C₁₋₆ alkyl group (the C₁₋₆ alkyl group isoptionally substituted with 1 to 5 halogen atom(s)), and a C₁₋₆ alkoxygroup (the C₁₋₆ alkoxy group is optionally substituted with 1 to 5halogen atom(s)). q is preferably an integer of 0 to 2. R^(10f) ispreferably a hydrogen atom or a C₁₋₆ alkyl group, more preferably ahydrogen atom or a methyl group.

Specific examples of Formula (A3)-IV include4-methyl-2-(4-trifluoromethylphenyl)thiazol-5-yl and4-methyl-2-(4-butoxy-3-chlorophenyl)thiazol-5-yl. Specific examples ofFormula (A3)-IV of the present specification also include groups of thesame formula as Formula (A3)-IV of the present specification in WO2008/030520 pamphlet, that is, the corresponding groups in groups ofFormula VIIC in p. 8, particularly the corresponding groups shown inExamples.

[1-13-e-8] The ring A in Formula (I), Formula (A)-IV, or Formula (A2)-IVis preferably the Partial Structural Formula (A4)-IV:

(where Z₁, Z₂, and Z₃ are the same as defined in Formula (A2)-IVdescribed in Aspect [1-13-e-3] (with the proviso that R^(10e) andR^(10f) are independently a hydrogen atom, a methyl group, or a methoxygroup); X₂ is —CH₂CH₂—, —CH═CH—, or —N(R_(z1))CH₂—; and R_(z1) is ahydrogen atom or a C₁₋₃ alkyl group).

In Formula (A4)-IV, preferably, Z₁ is —CR^(10e)—, R^(10e) is a hydrogenatom or a methyl group, Z₂ is a sulfur atom, Z₃ is —CR^(10f)—, andR^(10f) is a hydrogen atom. X₂ is —CH═CH— or —N(R_(z1)) CH₂— and R_(z1)is a methyl group.

Specific examples of Formula (A4)-IV include5-(spiro[inden-1,4′-piperidin]-1′-ylmethyl)-2-thienyl,4-methyl-5-(spiro[inden-1,4′-piperidin]-1′-ylmethyl)-2-thienyl, and5-(1-methylspiro[indolin-3,4′-piperidin]-1′-ylmethyl)-2-thienyl.Specific examples of Formula (A4)-IV of the present specification alsoinclude groups of the same formula as Formula (A4)-IV of the presentspecification in WO 2011/066183 pamphlet, particularly the correspondinggroups shown in Examples.

[1-13-e-9] In Formula (A)-IV, Formula (A1)-IV, or Formula (A2)-IV, morepreferable examples of R⁸ include a C₁₋₆ alkoxy group (the C₁₋₆ alkoxygroup is substituted with 1 to 5 —OH, 1 to 5 methoxy, 1 to 5 ethoxy, 1to 5 methysulfonyl, 1 to 5 sulfamoyl, 1 to 5 methysulfamoyl, 1 to 5dimethysulfamoyl, 1 to 5 carbamoyl, 1 to 5 methylcarbamoyl, 1 to 5dimethylcarbamoyl, 1 to 5—NH₂, 1 to 5 acetylamino, 1 to 5methysulfonylamino, 1 to 5 2-oxo-1-pyrrolidinyl, 1 to 55-oxo-2-pyrrolidinyl, or 1 to 5 3-methyloxetane-3-yl), a—CONR^(d4)R^(e4) group (R^(d4) is a hydrogen atom or a C₁₋₄ alkyl group;and R^(e4) is a C₁₋₆ alkyl group (the C₁₋₆ alkyl group is substitutedwith 1 to 5 —OH, 1 to 5 methoxy, 1 to 5 ethoxy, 1 to 5 methylsulfonyl, 1to 5 sulfamoyl, 1 to 5 methylsulfamoyl, 1 to 5 dimethylsulfamoyl, 1 to 5carbamoyl, 1 to 5 methylcarbamoyl, 1 to 5 dimethylcarbamoyl, 1 to 5—NH₂,1 to 5 acetylamino, 1 to 5 methylsulfonylamino, 1 to 52-oxo-1-pyrrolidinyl, 1 to 5 5-oxo-2-pyrrolidinyl, or 1 to 53-methyloxetane-3-yl), (1,1-dioxidetetrahydro-2H-thiopyran-4-yl)oxy, and(pyrrolidine-1-yl)carbonyl. The substitution number of —OH, methoxy,ethoxy, methylsulfonyl, sulfamoyl, methylsulfamoyl, dimethylsulfamoyl,carbamoyl, methylcarbamoyl, dimethylcarbamoyl, —NH₂, acetylamino,methylsulfonylamino, 2-oxo-1-pyrrolidinyl, 5-oxo-2-pyrrolidinyl, or3-methyloxetane-3-yl is preferably 1 to 2.

More specific examples of R⁸ include 2-hydroxyethoxy, 3-hydroxypropoxy,3-hydroxybutoxy, 3-hydroxy-3-methylbutoxy, 2,3-dihydroxypropoxy,(2R)-2,3-dihydroxypropoxy, (2S)-2,3-dihydroxypropoxy,(3S)-3-hydroxybutoxy, (3R)-3-hydroxybutoxy,3-hydroxy-2-hydroxymethylpropoxy,3-hydroxy-2-hydroxymethyl-2-methylpropoxy, 2-aminoethoxy,3-aminopropoxy, 2-(2-oxo-1-pyrrolidinyl)ethoxy,3-(2-oxo-1-pyrrolidinyl)propoxy, (5-oxo-2-pyrrolidinyl)methoxy,2-ethoxyethoxy, 2-methylsulfonylethoxy, 3-methylsulfonyl-propoxy,(1,1-dioxidetetrahydro-2H-thiopyran-4-yl)oxy,(4-hydroxy-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)methoxy,(3-methyloxetane-3-yl)methoxy, 2-acetylamino-ethoxy,2-acetylamino-ethoxy, 3-acetylamino-propoxy,2-methylsulfonylamino-ethoxy, 3-methylsulfonylamino-propoxy,2-carbamoyl-ethoxy, 3-carbamoyl-propoxy, 2-methylcarbamoyl-ethoxy,3-methylcarbamoyl-propoxy, 2-dimethylcarbamoyl-ethoxy,3-dimethylcarbamoyl-propoxy, 2-sulfamoyl-ethoxy, 3-sulfamoyl-propoxy,2-methylsulfamoyl-ethoxy, 3-methylsulfamoyl-propoxy,2-dimethylsulfamoyl-ethoxy, 3-dimethylsulfamoyl-propoxy,N-(2-hydroxyethyl)carbamoyl, N-(2-methoxyethyl)carbamoyl,N-(2-hydroxyethyl)-N-methylcarbamoyl,N-(2-methoxyethyl)-N-methylcarbamoyl,N-(2-methylsulfonyl-ethyl)carbamoyl,N-(2-methylsulfonyl-ethyl)-N-methylcarbamoyl, and(pyrrolidine-1-yl)carbonyl.

[1-13-e-10] In Formula (A)-IV, Formula (A1)-IV, Formula (A2)-IV, orFormula (A3)-IV, preferable examples of R⁹ and R¹⁰ independently includea halogen atom, a cyano group, a C₁₋₄ alkyl group (the C₁₋₄ alkyl groupis optionally substituted with 1 to 5 halogen atom(s) or 1 to 5 —OH), aC₁₋₄ alkoxy group which is optionally substituted with 1 to 5 halogenatom(s), a C₂₋₄ alkenyl group, a C₂₋₅ alkanoyl group, a —S(O)_(i)R^(a)(i is 2; and R^(a) is a C₁₋₄ alkyl group) group, a —CONR^(d)R^(e) (R^(d)and R^(e) are independently a hydrogen atom or a C₁₋₄ alkyl group)group, and a —NR^(b1)R^(c1) group (R^(b1) and R^(c1) form, together witha nitrogen atom to which they are bonded, a 3- to 8-membered cyclicgroup; and in the cyclic group, one or two carbon atom(s) is(are)optionally substituted with an oxygen atom, a nitrogen atom, or acarbonyl group). More specific examples of R⁹ and R¹⁰ include a fluorineatom, a chlorine atom, a bromine atom, cyano, methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, trifluoromethyl,hydroxymethyl, 2-hydroxyethyl, methoxy, ethoxy, trifluoromethoxy,trifluoroethoxy, vinyl, acetyl, methylsulfonyl, carbamoyl,methylcarbamoyl, dimethylcarbamoyl, 1-piperidinyl, 4-morpholinyl, and2-oxooxazolidin-3-yl. More preferable examples of R⁹, R^(9a), and R^(9b)include a fluorine atom, methyl, and methoxy, and more preferableexamples of R¹⁰ include methyl.

[1-13-e-11] In Formula (A)-IV, Formula (A1)-IV, or Formula (A2)-IV,preferable aspects of the ring A′ moiety having (R⁸)_(s), and (R⁹)_(q)are the same groups as the groups having an aryl group or a heteroarylgroup among the preferable aspects of L described in Aspect [1-1-d].Specific examples of the ring A′ moiety having (R⁸)_(s) and (R⁹)_(q)include the same groups as specific examples of the “aryl group which isoptionally substituted with 1 to 5 substituent(s) RII” or the groupshaving a heteroaryl group among specific examples of the “heterocyclicgroup which is optionally substituted with 1 to 5 substituent(s) RII”that are described in Aspect [1]. More specific examples thereof includethe same groups as the groups having benzene, naphthalene, pyridine,pyrimidine, thiophene, quinoline, or dibenzofuran.

[1-13-f] The ring A in Formula (I) is preferably Partial StructuralFormula (A)-V:

(where q, r, s, R⁸, R⁹, and R¹⁰ are the same as defined in Formula (A)described in Aspect [1-13-c]; n1 is an integer of 0 to 4; n2 is aninteger of 1 to 4, n3 is an integer of 0 to 2 (with the proviso thatn2+n3 is an integer of 2 to 4); X₃s are independently —CR^(v1)R_(v2)— or—NR_(v3)—; R_(v1), R_(v2), and R_(o) are independently a hydrogen atom,R⁸, or R⁹; and the broken lines in the ring are a single bond or adouble bond). In Formula (A)-V, the binding positions of R⁸, R⁹, and R¹⁰are any positions at which they can be optionally bonded in the ring.Here, in Formula (A)-V, R⁹ and R¹⁰ may be, in addition to the abovedescription, —OH or an oxo group, and R⁸ may be, in addition to theabove description, —NHR_(v4) (R_(v4) is a C₁₋₆ alkyl group (the C₁₋₆alkyl group is optionally substituted with 1 to 5 group(s) optionallyselected from —OH, a C₁₋₆ alkoxy group, a non-aromatic heterocyclicgroup (the heterocyclic group is optionally substituted with 1 to 2 C₁₋₄alkyl group(s) or 1 to 2 oxo group(s)), and a —S(O)_(i)R^(a) (i is aninteger of 0 to 2) group) or a C₂₋₇ alkanoyl group (the C₂₋₇ alkanoylgroup is optionally substituted with 1 to 5 group(s) optionally selectedfrom —OH, a C₁₋₆ alkoxy group, a non-aromatic heterocyclic group (theheterocyclic group is optionally substituted with 1 to 2 C₁₋₄ alkylgroup(s) or 1 to 2 oxo group(s)), and a —S(O)_(i)R^(a) (i is an integerof 0 to 2) group)). These substituents are the same as or different fromeach other and are optionally substituted with 1 to 5 group(s) in thespiro ring.

[1-13-f-1] In Formula (A)-V, X₃ is preferably —CR_(v1)R_(v2)— (R_(v1)and R_(v2) are the same as defined in Formula (A)-V).

[1-13-f-2] In Formula (A)-V, preferably, n1 is an integer of 0 to 4, n2is an integer of 1 to 3, and n3 is 1 or 2. More preferably, n1 is 2 or3, n2 is 1 or 2, and n3 is 1.

[1-13-f-3] In Formula (A)-V, preferably, q is an integer of 0 to 2 and ris an integer of 0 to 2. More preferably, q and r are 0.

[1-13-f-4] In Formula (A)-V, s is preferably 0 or 1. More preferably, sis 0.

[1-13-f-5] More preferable examples of Formula (A)-V include Formula(A1)-V:

(where n1, n2, and the broken lines are the same as defined in Formula(A)-V). In Formula (A1)-V, most preferably, n1 is 2 or 3 and n2 is 1 or2.

Specific examples of Formula (A)-V or Formula (A1)-V include spiro[4,5]dec-6-ene-7-yl, spiro[5,5]undec-2-yl, spiro[5,5]undec-1-ene-2-yl, andspiro[5,5]undec-2-ene-2-yl.

Specific examples of Formula (A)-V or Formula (A1)-V of the presentspecification also include groups of the same formula as Formula (A)-Vor Formula (A1)-V of the present specification in WO 2009/054479pamphlet, that is, the groups of the Spiro ring AB in the item 2 in p. 4to 5, particularly the corresponding groups shown in Examples.

[1-13-f-6] In Formula (A)-V, preferable examples of R⁹ and R¹⁰independently include a halogen atom, a C₁₋₄ alkyl group which isoptionally substituted with 1 to 5 halogen atom(s), a C₁₋₄ alkoxy groupwhich is optionally substituted with 1 to 5 halogen atom(s), an —OHgroup, and an oxo group. More specific examples of R⁹ and R¹⁰ include afluorine atom, a chlorine atom, a bromine atom, methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, trifluoromethyl,methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, and —OH. Morepreferable examples of R⁹ include a fluorine atom, methyl, methoxy, and—OH, and more preferable examples of R¹⁰ include methyl and —OH.

Specific examples of Formula (A)-V of the present specification alsoinclude the corresponding groups of the spiro ring AB substituted with asubstituent (an —OH group, a C₁₋₆ alkyl group, a C₁₋₆ alkoxy group, oran oxo group) in a formula of Formula [Ia.] of WO 2009/054479 pamphlet)as a group substituted with R⁹ or R¹⁰ in Formula (A)-V, particularly thecorresponding groups shown in Examples.

[1-13-f-7] In Formula (A)-V, preferable examples of R⁸s independentlyinclude a C₁₋₆ alkoxy group (the C₁₋₆ alkoxy group is substituted with 1to 5 group(s) optionally selected from —OH, a C₁₋₆ alkoxy group, anon-aromatic heterocyclic group (the heterocyclic group is optionallysubstituted with 1 to 2 C₁₋₄ alkyl group(s) or 1 to 2 oxo group(s)), anda —S(O)_(i)R^(a) (i is an integer of 0 to 2) group), a —CONR^(d3)R^(e3)group (R^(d3) is a hydrogen atom or a C₁₋₄ alkyl group; and R^(e3) is aC₁₋₆ alkyl group (the C₁₋₆ alkyl group is substituted with 1 to 5group(s) optionally selected from —OH, a C₁₋₆ alkoxy group, anon-aromatic heterocyclic group (the heterocyclic group is optionallysubstituted with 1 to 2 C₁₋₄ alkyl group(s) or 1 to 2 oxo group(s)), anda —S(O)_(i)R^(a) (i is an integer of 0 to 2) group)), an aralkyloxygroup, a non-aromatic heterocyclic oxy group (the heterocyclic oxy groupis optionally substituted with 1 to 2 oxo group(s)), a non-aromaticheterocyclic carbonyl group (the heterocyclic carbonyl group isoptionally substituted with 1 to 2 oxo group(s)), and —NHR_(v4) (R_(v4)is a C₁₋₆ alkyl group (the C₁₋₆ alkyl group is optionally substitutedwith 1 to 5 group(s) optionally selected from —OH, a C₁₋₆ alkoxy group,a non-aromatic heterocyclic group (the heterocyclic group is optionallysubstituted with 1 to 2 C₁₋₄ alkyl group(s) or 1 to 2 oxo group(s)), anda —S(O)_(i)R^(a) (i is an integer of 0 to 2) group) or a C₂₋₇ alkanoylgroup (the C₂₋₇ alkanoyl group is optionally substituted with 1 to 5group(s) optionally selected from —OH, a C₁₋₆ alkoxy group, anon-aromatic heterocyclic group (the heterocyclic group is optionallysubstituted with 1 to 2 C₁₋₄ alkyl group(s) or 1 to 2 oxo group(s)), anda —S(O)_(i)R^(a) (i is an integer of 0 to 2) group)). More specificexamples of R⁸ include a C₁₋₆ alkoxy group which is substituted with 1to 2 —OH, 1 to 2 methoxy, 1 to 2 ethoxy, 1 to 2 2-oxo-1-pyrrolidinyl, 1to 2 5-oxo-2-pyrrolidinyl, 1 to 2 3-methyloxetane-3-yl, or 1 to 2methylsulfonyl; a —CONR^(d4)R^(e4) group (R^(d4) is a hydrogen atom or aC₁₋₄ alkyl group; and R^(e4) is a C₁₋₆ alkyl group (the C₁₋₆ alkyl groupis substituted with 1 to 5 —OH, 1 to 5 methoxy, 1 to 5 ethoxy, 1 to 52-oxo-1-pyrrolidinyl, 1 to 5 5-oxo-2-pyrrolidinyl, 1 to 53-methyloxetane-3-yl, or 1 to 5 methylsulfonyl)), an aralkyloxy group,(1,1-dioxidetetrahydro-2H-thiopyran-4-yl)oxy,(pyrrolidine-1-yl)carbonyl, and —NHR_(v4) (R_(v4) is a C₁₋₆ alkyl group(the C₁₋₆ alkyl group is optionally substituted with 1 to 2 —OH, 1 to 2ethoxy, 1 to 2 2-oxo-1-pyrrolidinyl, 1 to 2 5-oxo-2-pyrrolidinyl, 1 to 23-methyloxetane-3-yl, or 1 to 2 methylsulfonyl) or a C₂₋₇ alkanoyl group(the C₂₋₇ alkanoyl group is optionally substituted with 1 to 2 —OH, 1 to2 ethoxy, 1 to 2 2-oxo-1-pyrrolidinyl, 1 to 2 5-oxo-2-pyrrolidinyl, 1 to2 3-methyloxetane-3-yl, or 1 to 2 methylsulfonyl)).

[1-13-f-8] The ring A in Formula (I) is preferably Partial StructuralFormula (AA)-V:

(where R^(13a) is the same as defined in Formula (AA) described inAspect [1-13-d]; r is the same as defined in Formula (A) described inAspect [1-13-c]; R¹⁰ is the same as defined in Formula (A)-V describedin Aspect [1-13-f]; n4 is an integer of 1 to 3; and the broken lines area single bond, a double bond, or the binding position of R^(13a)).

[1-13-f-9] The preferable aspects of R^(13a) in Formula (AA)-V are thesame as the preferable aspects described in Aspects [1-13-d-11] to[1-13-d-11-3]. More preferably, R^(13a) is a group of Formula (A′)-V—.

[1-13-f-10] Preferable examples of the ring A in Formula (I) or Formula(AA)-V include Formula (AA1)-V:

(where q, r, s, the ring A′, V, R⁸, and R⁹ are the same as defined inFormula (A) described in Aspect [1-13-c]; R¹⁰ and the broken line arethe same as defined in Formula (A)-V described in Aspect [1-13-f]; andn4 is the same as defined in Formula (AA)-V).

[1-13-f-11] In Formula (AA)-V or Formula (AA1)-V, n4 is preferably 1 or2, more preferably 2.

[1-134-12] In Formula (AA)-V or Formula (AA1)-V, r is preferably aninteger of 0 to 2. In Formula (AA1)-V, q is preferably an integer of 0to 3, more preferably an integer of 0 to 2. s is preferably 0 or 1. Morepreferably, any one of q and s is 1 or more.

[1-13-f-13] In Formula (AA1)-V, the preferable aspects of the ring A′,R⁸, and R⁹ are the same as the preferable aspects described in Aspects[1-13-c-2], [1-13-c-7] to [1-13-c-7-2], and [1-13-c-8]. The preferableaspects of the ring A′ moiety having (R⁸)_(s) and (R⁹)_(q) are the sameas the preferable aspects described in Aspect [1-13-c-10].

In Formula (AA)-V or Formula (AA1)-V, the preferable aspects of R¹⁰ arethe same as the preferable aspects described in Aspect [1-13-f-6].

[1-13-g] The ring A in Formula (I) is preferably Partial StructuralFormula (A)-VI:

(where R^(x), R^(xa), and X₁ are the same as defined in Formula (SP)described as the “substituted spiropiperidinyl group” in Aspect [1]; andR_(xb) is a group selected from a hydrogen atom, a fluorine atom, achlorine atom, C₁₋₃ alkyl, trifluoromethyl, and methoxy).

[1-13-g-1] In Formula (A)-VI, preferably, at least any one of R_(x) andR_(xa) is a hydrogen atom. More preferably, R_(xa) is a hydrogen atomand R_(x) is a group selected from a hydrogen atom, a fluorine atom,methyl, trifluoromethyl, and methoxy, or R_(xa) is a hydrogen atom or achlorine atom and R_(x) is a hydrogen atom, or both of R_(x) and R_(xa)are a hydrogen atom.

In Formula (A)-VI, R_(xb) is preferably a group selected from a hydrogenatom, methyl, trifluoromethyl, and methoxy, more preferably a hydrogenatom.

In Formula (A)-VI, X₁ is preferably —CH(R_(y))CH₂—, —C(R_(y))═CH—, or—N(R_(z))CH₂, more preferably —C(R_(y))═CH— or —N(R_(z))CH₂.

In Formula (A)-VI, R_(y) is preferably a hydrogen atom or methyl, morepreferably a hydrogen atom.

In Formula (A)-VI, R_(z) is preferably a hydrogen atom or C₁₋₃ alkyl,more preferably methyl.

Specifically, in Aspect [1-13-g], examples of Partial Structural Formula(SP)—CH₂—:

in Formula (A)-VI include a group selected from any ofspiro[indan-1,4′-piperidin]-1′-ylmethyl,(1′H-spiro[inden-1,4′-piperidin]-1′-yl)methyl,1,2-dihydro-1′H-spiro[indol-3,4′-piperidin]-1′-ylmethyl,(1-methyl-1,2-dihydro-1′H-spiro [indol-3,4′-piperidin]-1′-yl)methyl,{1-(1-methylethyl)-1,2-dihydro-1′H-spiro[indol-3,4′-piperidin]-1′-yl}methyl,(1-phenyl-1,2-dihydro-1′H-spiro[indol-3,4′-piperidin]-1′-yl)methyl,(2,3-dihydro-1′H-spiro[inden-1,4′-piperidin]-1′-ylmethyl,(7-chloro-1-methyl-1,2-dihydro-1′H-spiro[indol-3,4′-piperidin]-1′-yl)methyl,(5-fluoro-1-methyl-1,2-dihydro-1′H-spiro[indol-3,4′-piperidin]-1′-yl)methyl,(5-methoxy-1-methyl-1,2-dihydro-1′H-spiro[indol-3,4′-piperidin]-1′-yl)methyl,(1,5-dimethyl-1,2-dihydro-1′H-spiro[indol-3,4′-piperidin]-1′-yl)methyl,[1-methyl-5-(trifluoromethyl)-1,2-dihydro-1′H-spiro[indol-3,4′-piperidin]-1′-yl)methyl,and (3-oxo-2,3-dihydro-1′H-spiro[inden-1,4′-piperidin]-1′-yl)methyl.

[1-13-g-2] Preferable examples of the ring A in Formula (I) includePartial Structural Formula (AA)-VI:

(where q, s, R⁸, and R⁹ are the same as defined in Formula (A) describedin Aspect [1-13-c]; R_(xb) is the same as defined in Formula (A)-VIdescribed in Aspect [1-13-g]; and the broken lines indicate the bindingposition of a piperidinylmethyl group).

The preferable aspects of q, s, R⁸, and R⁹ in Formula (AA)-VI are thesame as the preferable aspects described in Aspects [1-13-c-3],[1-13-c-5], [1-13-c-7] to [1-13-c-7-2], or [1-13-c-8].

[1-13-h] The ring A in Formula (I) is preferably Partial StructuralFormula (A)-VII:

(where T is the same as defined in Formula (AA) described in Aspect[1-13-d]; R_(x), R_(xa), and X₁ are the same as defined in Formula (SP)described as the “substituted spiropiperidinyl group” in Aspect [1];R_(xb) is the same as defined in Formula (A)-VI described in Aspect[1-13-g]; R_(xc) is a group selected from a hydrogen atom, a fluorineatom, a chlorine atom, C₁₋₃ alkyl, trifluoromethyl, and methoxy; and thebroken lines and the Figures 4 and 5 indicate the binding position ofthe substituted spiropiperidinylmethyl group).

[1-13-h-1] Preferable examples of the ring A in Formula (I) includePartial Structural Formula (AA)-VII:

(where T is the same as defined in Formula (AA) described in Aspect[1-13-d]; q, s, R⁸, and R⁹ are the same as defined in Formula (A)described in Aspect [1-13-c]; R_(xb) is the same as defined in Formula(A)-VI described in Aspect [1-13-g]; R_(xc) is the same as defined inFormula (A)-VII described in Aspect [1-13-h]; and the broken linesindicate the binding position of the piperidinylmethyl group).

The preferable aspects of q, s, R⁸, and R⁹ in Formula (AA)-VII are thesame as the preferable aspects described in Aspects [1-13-c-3],[1-13-c-5], [1-13-c-7] to [1-13-c-7-2], or [1-13-c-8].

[1-13-i] Preferable examples of the ring A in Formula (I) includephthalazinyl which is optionally substituted with 1 to 5 L(s).

Specific examples of phthalazinyl which is optionally substituted with 1to 5 L(s) include 4-chloro-1-phthalazinyl,4-trifluoromethyl-1-phthalazinyl, 4-cyano-1-phthalazinyl, and4-cyclopropylmethoxy-1-phthalazinyl.

Specific examples of the ring A of the present specification alsoinclude the groups of G in Formula (I) and the like in WO 2010/091176pamphlet, particularly the corresponding groups shown in Examples.

[1-13-j] Preferable examples of the ring A in Formula (I) includePartial Structural Formula (A)-VIII:

(where r2 is an integer of 0 to 4; n5 is 1 or 2;

-   D is —CO—CR^(14b)R^(14c)— or —(CR^(14b)R^(14c))_(m)(m is 1 or 2)-; E    is —CR^(14d)R^(14e)—;-   L₁ is a group optionally selected from a C₁₋₁₀ alkyl group (the    C₁₋₁₀ alkyl group is optionally substituted with 1 to 5 halogen    atom(s)), an aryl group (the aryl group is optionally substituted    with 1 to 5 halogen atom(s), 1 to 5 C₁₋₆ alkyl group(s), or 1 to 5    halogenated C₁₋₆ alkyl group(s)), a heterocyclic group (the    heterocyclic group is optionally substituted with 1 to 5 halogen    atom(s), 1 to 5 C₁₋₆ alkyl group(s), or 1 to 5 halogenated C₁₋₆    alkyl group(s)), an aralkyl group (the aralkyl group is optionally    substituted with 1 to 5 halogen atom(s), 1 to 5 C₁₋₆ alkyl group(s),    or 1 to 5 halogenated C₁₋₆ alkyl group(s)), a heteroarylalkyl group    (the heteroarylalkyl group is optionally substituted with 1 to 5    halogen atom(s), 1 to 5 C₁₋₆ alkyl group(s), or 1 to 5 halogenated    C₁₋₆ alkyl group(s)), a C₂₋₇ alkanoyl group, and a —S(O)_(i)R^(a) (i    is an integer of 0 to 2; and R^(a) is the same as defined in Formula    (I)) group;-   R^(14a)s are independently a halogen atom, a C₁₋₆ alkyl group (the    C₁₋₆ alkyl group is optionally substituted with 1 to 5 halogen    atom(s)), or a C₁₋₆ alkoxy group (the C₁₋₆ alkoxy group is    optionally substituted with 1 to 5 halogen atom(s)); and R^(14b),    R^(14c), R^(14d), and R^(14e), are independently a hydrogen atom, a    halogen atom, or a C₁₋₆ alkyl group (the C₁₋₆ alkyl group is    optionally substituted with 1 to 5 halogen atom(s)); and R^(14c) and    R^(14e) optionally form, together with a carbon atom to which they    are bonded, a 5- to 6-membered aryl group or heteroaryl group (ring    B1)).

In Formula (A)-VIII, L₁ is preferably a group optionally selected from aC₁₋₄ alkyl group (the C₁₋₄ alkyl group is optionally substituted with 1to 5 halogen atom(s)), a heteroaryl group (the heteroaryl group isoptionally substituted with 1 to 5 halogen atom(s), 1 to 5 C₁₋₄ alkylgroup(s), or 1 to 5 halogenated C₁₋₄ alkyl group(s)), and a—S(O)_(i)R^(a) (i is an integer of 0 to 2; and R^(a) is the same asdefined in Formula (I)) group.

Specific examples of Formula (A)-VIII include1,2,3,4-tetrahydro-1-oxo-2-(2,2,2-trifluoroethyl)-4-isoquinolyl,2-cycloprop-ylmethyl-1,2,3,4-tetrahydro-1-oxo-4-isoquinolyl,1,2,3,4-tetrahydro-2-(2-methylpropyl)-1-oxo-4-isoquinolyl,1-(5-fluoro-2-pyridinyl)-3-piperidinyl,1-(5-trifluoromethyl-2-pyridinyl)-3-piperidinyl,1,2,3,4-tetrahydro-1-methylsulfonyl-4-quinolyl,8-fluoro-1,2,3,4-tetrahydro-1-methylsulfonyl-4-quinolyl,1,2,3,4-tetrahydro-1-(2,2,2-trifluoroethyl)-4-quinolyl, and8-fluoro-1,2,3,4-tetrahydro-1-(2,2,2-trifluoroethyl)-4-quinolyl.

Specific examples of the ring A and Formula (A)-VIII of the presentspecification also include the cyclic group containing D and E inFormula (I) and the like in WO 2010/085525 pamphlet, particularly thecorresponding groups shown in Examples.

[1-13-k] Preferable examples of the ring A in Formula (I) include a2-phenylamino-2-oxoacetyl group which is optionally substituted with 1to 5 L(s) and more preferable examples thereof include PartialStructural Formula (A)-IX:

(where R_(x3) is a group optionally selected from a hydrogen atom, ahalogen atom, a C₁₋₈ alkyl group (the C₁₋₈ alkyl group is optionallysubstituted with 1 to 5 halogen atom(s)), a trifluoromethoxy group, aphenyl group, and a —COOR^(f) group;

-   R_(x1) and R_(x5) are independently a group optionally selected from    a hydrogen atom, a halogen atom, a C₁₋₆ alkyl group (the C₁₋₆ alkyl    group is optionally substituted with 1 to 5 halogen atom(s)), a    phenyl group, and a —COOR^(f) group;-   R_(x2) and R_(x4) are independently a group optionally selected from    a hydrogen atom, a halogen atom, a C₁₋₆ alkyl group (the C₁₋₆ alkyl    group is optionally substituted with 1 to 5 halogen atom(s)), and a    —COOR^(f) group; and-   R^(f) is a hydrogen atom or a C₁₋₆ alkyl group).

In Formula (A)-IX, R_(x3) is preferably a hydrogen atom, a halogen atom,a C₁₋₆ alkyl group, a trifluoromethyl group, a methoxycarbonyl group, ora phenyl group. R_(x1) and R_(x5) are preferably independently ahydrogen atom, a halogen atom, a methyl group, a trifluoromethyl group,a methoxycarbonyl group, or a phenyl group. R_(x2) and R_(x4) arepreferably independently a hydrogen atom, a halogen atom, or atrifluoromethyl group.

Specific examples of Formula (A)-IX include2-((2-bromo-4-isopropylphenyl)amino)-2-oxoacetyl,2((4-isopropyl-2-(trifluoromethyl)phenyl)amino)-2-oxoacetyl,2-((2,4-bis(trifluoromethyl)phenyl)amino)-2-oxoacetyl, and2-((4-bromo-3-chlorophenyl)amino)-2-oxoacetyl.

Specific examples of the ring A and Formula (A)-IX of the presentspecification also include the groups of the same formula as Formula(A)-IX of the present specification in Formula (I) in WO 2009/039943pamphlet, particularly the corresponding groups shown in Examples.

[1-13-1] In the preferable Aspects [1-13-e-8], [1-13-g], and [1-13-h] ofthe ring A in Formula (I), an aspect in which each spiropiperidine ring(SP) is replaced with the above-described another spiropiperidine ring(SP′) is also a preferable aspect.

Accordingly, it can be understood that examples of the preferable aspectof the ring A in Formula (I) of the present invention include, inaddition to Aspects [1-13-e-8], [1-13-g], and [1-13-h], [1-13-e-8a],[1-13-ga], and [1-13-ha] below.

[1-13-e-8a] The ring A in Formula (I) is preferably Partial StructuralFormula (A5)-IVa:

(where Z₁, Z₂, and Z₃ are the same as defined in Formula (A2)-IVdescribed in Aspect [1-13-e-3]; and R^(6a), R^(7a), R^(8a), xa, andY^(1a) to Y^(4a) are the same as defined in the above Formula (SP′)).

In Formula (A5)-IVa, preferably, Z₁ is —CR^(10e)—, R^(10e) is a hydrogenatom or a methyl group, Z₂ is a sulfur atom, Z₃ is —CR^(10f)—, andR^(10f) is a hydrogen atom. X₂ is —CH═CH— or —N(R_(z1))CH₂—, and R_(z1)is a methyl group.

Specific examples of Formula (A5)-IVa include5-(spiro[isobenzofuran-1(3H),4′-piperidin]-1′-ylmethyl)-2-thienyl,5-(spiro[benzofuran-3(2H),4′-piperidin]-1′-ylmethyl)-2-thienyl,5-(spiro[6-azaisobenzofuran-1(3H),4′-piperidin]-1′-ylmethyl)-2-thienyl,5-(3-oxospiro[4-azaisobenzofuran-1(3H),4′-piperidin]-1′-ylmethyl)-2-thienyl,5-(3-oxospiro[6-azaisobenzofuran-1(3H),4′-piperidin]-1′-ylmethyl)-2-thienyl,5-(spiro[5-fluoroisobenzofuran-1(3H),4′-piperidin]-1′-ylmethyl)-2-thienyl,5-(spiro[6-fluoroisobenzofuran-1(3H),4′-piperidin]-1′-ylmethyl)-2-thienyl,5-(spiro[5-fluoro-6-azaisobenzofuran-1(3H),4′-piperidin]-1′-ylmethyl)-2-thienyl,5-(spiro[6-fluoro-5-azaisobenzofuran-1(3H),4′-piperidin]-1′-ylmethyl)-2-thienyl,and5-(7-fluoro-1H-spiro[fluoro[3,4-c]pyridin-3,4′-piperidin]-1′-ylmethyl)-2-thienyl.

[1-13-ga] The ring A in Formula (I) is preferably Formula (A)-VIa:

(where R_(xb) is a group selected from a hydrogen atom, a fluorine atom,a chlorine atom, C₁₋₃ alkyl, trifluoromethyl, and methoxy, morepreferably, a hydrogen atom; and R^(6a), R^(7a), R^(8a), xa, and Y^(1a)to Y^(4a) are the same as defined in Formula (SP′)).

Specific examples of the ring A include rings in which PartialStructural Formula (SP′)—CH₂—:

in Formula (A)-VIa is (spiro[isobenzofuran-1(3H),4′-piperidin]-1-yl)methyl, (spiro[benzofuran-3(2H),4′-piperidin]-1-yl)methyl, (3-oxospiro[6-azaisobenzofuran-1(3H),4′-piperidin]-1-yl)methyl, (spiro[5-fluoroisobenzofuran-1(3H),4′-piperidin]-1-yl)methyl, (spiro[6-fluoroisobenzofuran-1(3H),4′-piperidin]-1-yl)methyl, (spiro[5-fluoro-6-azaisobenzofuran-1(3H),4′-piperidin]-1-yl)methyl, (spiro[6-azaisobenzofuran-1(3H),4′-piperidin]-1-yl)methyl, (spiro[5-fluoroisobenzofuran-1(3H),4′-piperidin]-1-yl)methyl, (spiro[6-fluoroisobenzofuran-1(3H),4′-piperidin]-1-yl)methyl, (spiro[5-fluoro-6-azaisobenzofuran-1(3H),4′-piperidin]-1-yl)methyl, or (7-fluoro-1H-spiro[fluoro[3,4-c]pyridin-3,4′-piperidin]-1-yl)methyl.

[1-13-ha] The ring A in Formula (I) is preferably Partial StructuralFormula (A)-VIIa:

(where T is the same as defined in Formula (AA) described in Aspect[1-13-d]; the definitions of R^(6a), R^(7a), R^(8a), xa, and Y^(1a) toY^(4a) correspond to the definitions of R⁶, R⁷, R⁸, x, and Y¹ to Y⁴respectively in Formula [II] in WO 2002/088989 pamphlet; R_(xb) is agroup selected from a hydrogen atom, a fluorine atom, a chlorine atom,C₁₋₃ alkyl, trifluoromethyl, and methoxy, preferably a hydrogen atom;R_(xc) is a group selected from a hydrogen atom, a fluorine atom, achlorine atom, C₁₋₃ alkyl, trifluoromethyl, and methoxy, preferably ahydrogen atom; and the broken lines and the Figures 4 and 5 indicate thebinding position of the substituted spiropiperidinylmethyl group).

Specific examples of the ring A include rings in which PartialStructural Formula (SP′)—CH₂—:

in Formula (A)-VIIa is (spiro[isobenzofuran-1(3H),4′-piperidin]-1-yl)methyl, (spiro[benzofuran-3(2H),4′-piperidin]-1-yl)methyl, (3-oxospiro[6-azaisobenzofuran-1(3H),4′-piperidin]-1-yl)methyl, (spiro[5-fluoroisobenzofuran-1(3H),4′-piperidin]-1-yl)methyl, (spiro[6-fluoroisobenzofuran-1(3H),4′-piperidin]-1-yl)methyl, (spiro[5-fluoro-6-azaisobenzofuran-1(3H),4′-piperidin]-1-yl)methyl, (spiro[6-azaisobenzofuran-1(3H),4′-piperidin]-1-yl)methyl, (spiro[5-fluoroisobenzofuran-1(3H),4′-piperidin]-1-yl)methyl, (spiro[6-fluoroisobenzofuran-1(3H),4′-piperidin]-1-yl)methyl, (spiro[5-fluoro-6-azaisobenzofuran-1(3H),4′-piperidin]-1-yl)methyl, or (7-fluoro-1H-spiro[fluoro[3,4-c]pyridin-3,4′-piperidin]-1-yl)methyl.

[1-14] The group having the ring B and the cyclic amide structure ofFormula (I) according to Aspect [1] is Partial Structural Formula (B):

(where n, p, h, the ring B, J₁, J₂, R¹, R^(2a), and R^(2b) are the sameas defined in Formula (I) described in Aspect [1]).

[1-14-a] In Formula (B), when the ring B is a monocyclic ring, the ringB is preferably bonded to J₁.

[1-14-a-1] In Formula (B), when the ring B is a benzene ring, a pyridinering, or a pyrimidine ring, Formula (B) is preferably Formula (B)-1:

(where n, p, h, J₂, R¹, R^(2a), and R^(2b) are the same as defined inFormula (I) described in Aspect [1]; the ring B′ is a benzene ring, apyridine ring, or a pyrimidine ring; and J_(1a) is CR^(11a) or anitrogen atom).

[1-14-a-2] More preferable examples of Formula (B) include Formula (B 1)and Formula (B2):

(where n, p, h, J₂, R¹, R^(2a), and R^(2b) are the same as defined inFormula (I); and the ring B′ and J_(1a) are the same as defined inFormula (B)-1). When the binding position with the linker moietycontaining X is determined as 1-position, in Formula (B1), R¹ can bebonded at 2-position, 3-position, 5-position, and 6-position, and inFormula (B2), R¹ can be bonded at 2-position, 4-position, 5-position,and 6-position.

[1-14-a-3] Formula (B) or Formula (B)-1 is preferably Formula (B1).

[1-14-a-4] More preferable examples of Formula (B) or Formula (B)-1include Formula (B1a) and Formula (B 1b):

(where n, p, h, J₂, R¹, R^(2a), and R^(2b) are the same as defined inFormula (I); and J_(1a) is the same as defined in Formula (B)-1).

[1-14-a-5] Further preferable examples of Formula (B) or Formula (B)-1include Formula (B1a).

[1-14-b] When in Formula (B), the ring B is Formula (BB1) or Formula(BB2), Formula (B) is Formula (BB1)-1 or Formula (BB2)-1:

(where n, p, h, J₁, J₂, R¹, R^(2a), and R^(2b) are the same as definedin Formula (I) described in Aspect [1]; and G, W₁, W₂, and W₃ are thesame as in Formula (BB1) and Formula (BB2) described in Aspect [1-10]).Specifically, Formula (B) is preferably Formula (BB1)-1a, Formula(BB1)-1b, Formula (BB2)-1a, or Formula (BB2)-1b:

(where n, p, h, J₁, J₂, R¹, R^(2a), and R^(2b) are the same as definedin Formula (I) described in Aspect [1]; J_(1a) is the same as defined inFormula (B)-1; and G, W₁, W₂, and W₃ are the same as in Formula (BB1)and Formula (BB2) described in Aspect [1-10]). When J₂ is—CR^(12a)R^(12b)—, a structure in which Formula (BB1) or Formula (BB2)is bonded to J₂ adjacent to S in the cyclic amide structure, is alsopreferred.

[1-14-c] When the ring A is Formula (A) described in Aspect [1-13-c] andthe ring A′-V— is bonded at the m-position relative to the bindingposition with the linker moiety containing X, specifically when the ringA is Formula (A1a), Formula (A1b), Formula (A1c), or Formula (A1)-1-1described in Aspect [1-13-c-3-1] or Aspect [1-13-c-11], in Formula(B)-1, an isothiazolyl group is preferably bonded at the p-positionrelative to the binding position with the linker moiety containing X. Inaddition, when the ring A is Formula (AA1) described in Aspect[1-13-d-4] and R^(13a) is bonded at 4-position, or the ring A is Formula(AA1b) described in Aspect [1-13-d-7] and R^(13a) is bonded at7-position, specifically also when the ring A is Formula (AA1)-1,Formula (AA1a)-1, Formula (AA1a)-1-1, or Formula (AA1b)-1 described inAspects [1-13-d-5] to [1-13-d-7-1], in Formula (B)-1, an isothiazolylgroup is preferably bonded at the p-position relative to the bindingposition with the linker moiety containing X. Further, also when thering A is Formula (A)-IV, Formula (A1)-IV, Formula (A2)-IV, Formula(A3)-IV, or Formula (A4)-IV described in Aspects [1-13-e] to [1-13-e-8],Formula (A)-V, Formula (A1)-V, Formula (AA)-V, or Formula (AA1)-Vdescribed in Aspects [1-13-f] to [1-13-f-10], or Formula (A)-VI orFormula (AA)-VI described in Aspects [1-13-g] to [1-13-g-2], in Formula(B)-1, an isothiazolyl group is preferably bonded at the p-positionrelative to the binding position with the linker moiety containing X.

[1-14-c-1] When the ring A is Formula (A) described in Aspect [1-13-c]and the ring A′-V— is bonded at the p-position relative to the bindingposition with the linker moiety containing X, specifically when the ringA is Formula (A1)-1-2 described in Aspect [1-13-c-12], in Formula (B)-1,an isothiazolyl group is preferably bonded at the m-position relative tothe binding position with the linker moiety containing X.

[1-14-d] In Formula (B), Formula (B)-1, Formula (B1), Formula (B2),Formula (B1a), Formula (Bib), Formula (BB1)-1, Formula (BB2)-1, Formula(BB1)-1a, Formula (BB1)-1b, Formula (BB2)-1a, or Formula (BB2)-1b, R¹ ispreferably a halogen atom, a C₁₋₄ alkyl group which is optionallysubstituted with 1 to 5 halogen atom(s), a C₁₋₄ alkoxy group which isoptionally substituted with 1 to 5 halogen atom(s), or a cyano group,and more specifically, R¹ is preferably a fluorine atom, a chlorineatom, a bromine atom, methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, tert-butyl, trifluoromethyl, methoxy, ethoxy, propoxy,isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy,trifluoromethoxy, or cyano. p is preferably 0 or 1, more preferably 0.

In Formula (B), Formula (B)-1, Formula (B 1), Formula (B2), Formula(B1a), Formula (Bib), Formula (BB1)-1, Formula (BB2)-1, Formula(BB1)-1a, Formula (BB1)-1b, Formula (BB2)-1a, or Formula (BB2)-1b,R^(2a) and R^(2b) are preferably a hydrogen atom, a halogen atom, or aC₁₋₄ alkyl group. More specifically, R^(2a) and R^(2b) are preferably ahydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, ormethyl, and more preferably, any one of R^(2a) and R^(2b) is a hydrogenatom. Further preferably, both of R^(2a) and R^(2b) are a hydrogen atom.

In Formula (B), Formula (B)-1, Formula (B1), Formula (B2), Formula(B1a), Formula (B1b), Formula (BB1)-1, Formula (BB2)-1, Formula(BB1)-1a, Formula (BB1)-1b, Formula (BB2)-1a, or Formula (BB2)-1b, h ispreferably 0 or 1 and n is preferably 1 or 2. When J_(1a) is CR^(11a)and h is 0, n is more preferably 1. When J_(1a) is a nitrogen atom and his 0, n is more preferably 2. When h is an integer of 1 to 3, n is morepreferably 2.

[1-14-e] The cyclic amide structure bonded to the ring B in Formula (I),Formula (B), Formula (BB1)-1, or Formula (BB2)-1 is Partial StructuralFormula (B-Het):

(where n, h, J₁, J₂, R^(2a), and R^(2b) are the same as defined inFormula (I) described in Aspect [1]). In Formula (B-Het), the ring B canbe bonded at any position in the ring, specifically to a carbon atom towhich R^(2a) and R^(2b) are bonded, J₁, or J₂.

In Formula (I) or Formula (B), Formula (B-Het) is preferably Formula(B-Het)-1 or (B-Het)-2:

(where n, h, J₁, J₂, R^(2a), and R^(2b) are the same as defined inFormula (I) described in Aspect [1]; and J_(1a) is the same as definedin Formula (B)-1).

[1-14-e-1] More preferable examples of Formula (B-Het) or Formula(B-Het)-1 include Formula (B-Het)-1a, Formula (B-Het)-1b, Formula(B-Het)-1c, Formula (B-Het)-1d, Formula (B-Het)-1e, and Formula(B-Het)-1f:

where n, R^(2a), R^(2b), R^(11a), R^(12a), R^(12b), and R^(12c) are thesame as defined in Formula (I) described in Aspect [1]; and h1 is 1 or2).

More preferable examples of Formula (B-Het) or Formula (B-Het)-2 includeFormula (B-Het)-2a, Formula (B-Het)-2b, Formula (B-Het)-2c, Formula(B-Het)-2d, Formula (B-Het)-2e, Formula (B-Het)-2f, Formula (B-Het)-3c,and Formula (B-Het)-3f:

(wherein, R^(2a), R^(2b), R^(11a), R^(11b), R^(12a), R^(12b), R^(11c),and R^(12c) are the same as defined in Formula (I) described in Aspect[1]; and h1 is 1 or 2).

In Formula (I) according to Aspect [1], a compound in which the cyclicamide structure bonded to the ring B (that is, Formula (B-Het)) isFormula (B-Het)-1a is Formula (I)-1a. Similarly, the compound havingFormula (B-Het)-1b is Formula (I)-1b; the compound having Formula(B-Het)-1c is Formula (I)-1c; the compound having Formula (B-Het)-1d isFormula (I)-1d; the compound having Formula (B-Het)-1e is Formula(I)-1e; the compound having Formula (B-Het)-1f is Formula (I)-1f; thecompound having Formula (B-Het)-2a is Formula (I)-2a; the compoundhaving Formula (B-Het)-2b is Formula (I)-2b; the compound having Formula(B-Het)-2c is Formula (I)-2c; the compound having Formula (B-Het)-2d isFormula (I)-2d; the compound having Formula (B-Het)-2e is Formula(I)-2e; the compound having Formula (B-Het)-2f is Formula (I)-2f; thecompound having Formula (B-Het)-3c is Formula (I)-3c; and the compoundhaving Formula (B-Het)-3f is Formula (I)-3f.

In Formula (B-Het)-1a, n is preferably 1 or 2, and specifically, Formula(B-Het)-1a is Formula (B-Het)-1a1 or Formula (B-Het)-1a2:

(where R^(2a), R^(2b), and R^(11a) are the same as defined in Formula(I)).

[1-14-e-2] In each formula used for a compound in each aspect of Aspect[1], the Formula (B-Het) moiety can be accordingly selected from, forexample, Formulae (het1) to (het9):

The Formula (B-Het) moiety is particularly preferably Formulae (het1) to(het5) above.

[1-15] In a combination of j, k, X, R³, R⁴, R⁵, and R⁶, in Formula (I),the linker moiety containing X bonded to the ring A and the ring B isPartial Structural Formula (C):

(where j, k, X, R³, R⁴, R⁵, and R⁶ are the same as defined in Formula(I) described in Aspect [1]; and ● is a single bond with the ring A).

Preferable specific examples of Formula (C) include Formula (c1) toFormula (c6):

[1-15-a] More preferably, Formula (C) is Formula (c1), Formula (c2),Formula (c4), or Formula (c5).

[1-15-b] When the ring A is a monocyclic ring or a spiro ring, that is,when the ring A is a phenyl group, a monocyclic heterocyclic group, acycloalkyl group, a cycloalkenyl group, or a spiro ring group,specifically, when the ring A is Formula (A), Formula (A)-1, Formula(A1), Formula (A2), Formula (A1)-1, Formula (A2)-1, Formula (A1a),Formula (A1b), Formula (A1c), Formula (A1)-1-1, or Formula (A1)-1-2described in Aspects [1-13-c] to [1-13-c-12], Formula (A)-IV, Formula(A1)-IV, Formula (A2)-IV, Formula (A3)-IV, or Formula (A4)-IV describedin Aspects [1-13-e] to [1-13-e-8], Formula (A)-V, Formula (A1)-V,Formula (AA)-V, or Formula (AA1)-V described in Aspects [1-13-f] to[1-13-f-10], Formula (A)-VI or Formula (AA)-VI described in Aspects[1-13-g] to [1-13-g-2], or Formula (A5)-IVa or Formula (A)-VIa describedin Aspect [1-13-e-8a] or [1-13-ga], Formula (C) is further preferablyFormula (c2) or Formula (c5), most preferably Formula (c2).

[1-15-c] When the ring A is a fused ring, that is, when the ring A is aring-fused aryl group, a partly hydrogenated ring-fused aryl group, aring-fused heteroaryl group, a partly hydrogenated ring-fused heteroarylgroup, or a ring-fused non-aromatic heterocyclic group, specificallywhen the ring A is Formula (AA), Formula (AA)-1, Formula (AA)-1-1,Formula (AA1), Formula (AA1)-1, Formula (AA1a)-1, Formula (AA1a)-1-1,Formula (AA 1b), or Formula (AA1b)-1 described in Aspects [1-13-d] to[1-13-d-7-1], Formula (A)-VII or Formula (AA)-VII described in Aspect[1-13-h] or [1-13-h-1], a phthalazinyl group described in Aspect[1-13-i], Formula (A)-VIII described in Aspect [1-13-j], or Formula(A)-VIIa described in Aspect [1-13-ha], Formula (C) is furtherpreferably Formula (c1) or Formula (c4), most preferably Formula (c1).

[1-15-d] When the ring A is a 2-phenylamino-2-oxoacetyl group,specifically when the ring A is Formula (A)-IX described in Aspect[1-13-k], the linker moiety is preferably —NR⁷—, more preferably Formula(c4).

[1-16] The compound of Formula (I) according to Aspect [1] is preferablya compound of Formula (I)-1:

(where n, p, h, j, k, the ring A, X, J₂, R¹, R^(2a), R^(2b), R³, R⁴, R⁵,and R⁶ are the same as defined in Formula (I) described in Aspect [1];and the ring B′ and J_(1a) are the same as defined in Formula (B)-1described in Aspect [1-14-a-1] (with the proviso that a compound that is5-[4-[2-(2-phenyl-4-oxazolyl)ethoxy]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one;a compound in which a saturated cyclic amide structure having—S(O)_(n)—NH—CO— is 1,1-dioxo-1,2-thiazolidin-3-one, the ring B′ is abenzene ring, k is 1, and in the ring B′, the linker moiety containing Xand the cyclic amide structure are at the p-position; and a compound inwhich the cyclic amide structure is1,1-dioxo-1,2,5-thiadiazolidin-3-one, and in the ring B′, the cyclicamide structure is bonded to an atom adjacent to an atom to which thelinker containing X is bonded, are excluded)).

More specifically, the preferable aspects of n, p, h, j, k, the ring A,the ring B′, X, J_(1a), J₂, R¹, R^(2a), R^(2b), R³, R⁴, R⁵, and R⁶ arethe same as the preferable aspects described in any one of Aspects [1-1]to [1-15] and subordinate Aspects thereof. The preferable aspects of thepartial structure of Formula (I)-1 corresponding to the ring A, PartialStructural Formula (B)-1, Partial Structural Formula (B-Het)-1, orPartial Structural Formula (C) that are described in any one of Aspects[1-13], [1-14], and [1-15], and subordinate Aspects thereof are the sameas described in any one of Aspects [1-13], [1-14], and [1-15], andsubordinate Aspects thereof.

[1-16-1] The compound of Formula (I)-1 according to Aspect [1-16] ispreferably a compound in which the ring A is Formula (A), that is, acompound of Formula (II):

(where n, p, h, j, k, X, J₂, R¹, R^(2a), R^(2b), R³, R⁴, R⁵, R⁶ are thesame as defined in Formula (I) described in Aspect [1]; the ring B′ andJ_(1a) are the same as defined in Formula (B)-1 described in Aspect[1-14-a-1]; q, r, s, the ring A′, V, R⁸, R⁹, and R¹⁰ are the same asdefined in Formula (A) described in Aspect [1-13-c] (with the provisothat a compound in which the saturated cyclic amide structure having—S(O)_(n)—NH—CO— is 1,1-dioxo-1,2-thiazolidin-3-one, the ring B′ is abenzene ring, k is 1, and in the ring B′, the linker moiety containing Xand the cyclic amide structure are at the p-position is excluded)).

More specifically, the preferable aspects of n, p, q, r, s, h, j, k, thering A′, the ring B′, X, V, J_(1a), J₂, R¹, R^(2a), R^(2b), R³, R⁴, R⁵,R⁶, R⁸, R⁹, and R¹⁰ are the same as the preferable aspects described inany one of Aspects [1-1] to [1-15] and subordinate Aspects thereof. Thepreferable aspects of the partial structure of Formula (II)corresponding to Partial Structural Formula (A), Partial StructuralFormula (B)-1, Partial Structural Formula (B-Het)-1, or PartialStructural Formula (C) described in any one of Aspects [1-13-c], [1-14],and [1-15], and subordinate Aspects thereof are the same as described inany one of Aspects [1-13-c], [1-14], and [1-15], and subordinate Aspectsthereof.

The compound of Formula (II) is preferably a compound of Formula (II) inwhich the ring A′ is a benzene ring, a pyridine ring, or a pyrimidinering, that is, a compound in which the ring A is Formula (A)-1 inFormula (I), which is a compound of Formula (II)1:

(where n, p, h, j, k, X, J₂, R¹, R^(2a), R^(2b), R³, R⁴, R⁵, and R⁶ arethe same as defined in Formula (I) described in Aspect [1]; the ring B′and J_(1a) are the same as defined in Formula (B)-1 described in Aspect[1-14-a-1]; q, r, s, the ring A″, V, R⁸, R⁹, and R¹⁰ are the same asdefined in Formula (A) or Formula (A)-1 described in Aspect [1-13-c](with the proviso that a compound in which the saturated cyclic amidestructure having —S(O)_(n)—NH—CO— is 1,1-dioxo-1,2-thiazolidin-3-one,the ring B′ is a benzene ring, k is 1, and in the ring B′, the linkermoiety containing X and the cyclic amide structure are at the p-positionis excluded)).

More specifically, the preferable aspects of n, p, q, r, s, h, j, k, thering A″, the ring B′, X, V, J_(1a), J₂, R¹, R^(2a), R^(2b), R³, R⁴, R⁵,R⁶, R⁸, R⁹, and R¹⁰ are the same as the preferable aspects described inany one of Aspects [1-1] to [1-15] and the subordinate Aspects thereof.The preferable aspects of the partial structure of Formula (II)-1corresponding to Partial Structural Formula (A)-1, Partial StructuralFormula (B)-1, Partial Structural Formula (B-Het)-1, or PartialStructural Formula (C) described in any one of Aspects [1-13-c], [1-14],and [1-15], and the subordinate Aspects thereof are the same asdescribed in any one of Aspects [1-13-c], [1-14], and [1-15], andsubordinate Aspects thereof.

In Formula (II) or Formula (II)-1, X is preferably an oxygen atom or—NH—, more preferably an oxygen atom. In Formula (II) or Formula (II)-1,j is preferably 1. k is preferably 0. In Formula (II) or Formula (II)-1,more preferably, X is an oxygen atom and k is 0. Further preferably, Xis an oxygen atom, j is 1, and k is 0.

In Formula (II) or Formula (II)-1, in the ring B′, the linker moietycontaining X and the cyclic amide structure are preferably at thep-position, that is, the partial structure has preferably Formula (B1).The ring B′ is preferably a benzene ring.

In Formula (II) or Formula (II)-1, preferably, any one of q and s is 1or more, more preferably, s is 1.

In Formula (II) or Formula (II)-1, preferably, X is an oxygen atom, k is0, and any one of q and s is 1 or more, more preferably, X is an oxygenatom, k is 0, and s is 1.

[1-16-1a] In the compound of Formula (II), compounds produced byoptionally combining the groups of Partial Structural Formula (A) (onthe left of the left wavy line), Partial Structural Formula (B) (on theright of the right wavy line), Partial Structural Formula (C) (betweenthe two wavy lines) in Formula (II) can be produced optionally:

More specifically, Partial Structural Formula (A) is a group optionallyselected from Formula (A)-1, Formula (A1), Formula (A2), Formula (A1)-1,Formula (A2)-1, Formula (A1a), Formula (A1b), Formula (A1c), Formula(A1)-1-1, and Formula (A1)-1-2 described in Aspects [1-13-c] to[1-13-c-12]. Partial Structural Formula (B)-1 is a group optionallyselected from Formula (B 1), Formula (B2), Formula (B1a), and Formula(B1b) described in Aspects [1-14-a-2] and [1-14-a-4], and PartialStructural Formula (C) can be a group optionally selected from Formula(c1) to Formula (c6) described in Aspect [1-15]. An optional combinationof each formula forms part of the compound of Formula (I) according tothe present invention.

In the compound of Formula (II), preferably, Partial Structural Formula(A) is Formula (A2)-1 in which the ring A″-O— is bonded at 3-position,Formula (A1a), Formula (A1b), or Formula (A1c), Partial StructuralFormula (B)-1 is Formula (B1a) or Formula (Bib), and Partial StructuralFormula (C) is Formula (c2) or Formula (c5). More preferably, PartialStructural Formula (A) is Formula (A2)-1 in which the ring A″-O— isbonded at 3-position, Formula (A1a), or Formula (A1c), PartialStructural Formula (B)-1 is Formula (B1a), and Partial StructuralFormula (C) is Formula (c2). Further preferably, Partial StructuralFormula (B-Het)-1 in Partial Structural Formula (B)-1 is Formula(B-Het)-1a, Formula (B-Het)-1b, Formula (B-Het)-1c, Formula (B-Het)-1d,Formula (B-Het)-1e, or Formula (B-Het)-1f described in Aspect[1-14-e-1]. An optional combination of each formula forms part of thepreferable compound of Formula (I) according to the present invention.

[1-16-1-a] The compound of Formula (II) or Formula (II)-1 according toAspect [1-16-1] is preferably a compound of Formula (II)-1a:

(where n, p, j, k, X, R¹, R^(2a), R^(2b), R³, R⁴, R⁵, R⁶, and R¹¹ arethe same as defined in Formula (I); the ring B′ is the same as definedin Formula (B)-1 described in Aspect [1-14-a-1]; and q, r, s, the ringA″, V, R⁸, R⁹, and R¹⁰ are the same as defined in Formula (A) or Formula(A)-1 described in Aspect [1-13-c] (with the proviso that a compound inwhich the saturated cyclic amide structure having —S(O)_(n)—NH—CO— is1,1-dioxo-1,2-thiazolidin-3-one, the ring B′ is a benzene ring, k is 1,and in the ring B′, the linker moiety containing X and the cyclic amidestructure are at the p-position is excluded)), a salt of the compound,or a solvate of the compound or the salt.

More specifically, the preferable aspects of n, p, q, r, s, j, k, thering A″, the ring B′, X, V, R₁, R^(2a), R^(2b), R³, R⁴, R⁵, R⁶, R⁸, R⁹,R¹⁰, and R^(11a) are the same as preferable aspects described in any oneof Aspects [1-1] to [1-15] and subordinate Aspects thereof. Thepreferable aspects of the partial structure of Formula (II)-1acorresponding to Partial Structural Formula (A)-1, Partial StructuralFormula (B)-1, Partial Structural Formula (B-Het)-1a, or PartialStructural Formula (C) described in any one of Aspects [1-13-c], [1-14],and [1-15], and subordinate Aspects thereof are the same as described inany one of Aspects [1-13-c], [1-14], and [1-15], and subordinate Aspectsthereof.

In Formula (II)-1a, X is preferably an oxygen atom or —NH—, morepreferably an oxygen atom. In Formula (II)-1a, j is preferably 1. k ispreferably 0. In Formula (II)-1a, more preferably, x is an oxygen atomand k is 0. Further preferably, X is an oxygen atom, j is 1, and k is 0.

In Formula (II)-1a, in the ring B′, the linker moiety containing X andthe cyclic amide structure are preferably at the p-position. The ring B′is preferably a benzene ring.

In Formula (II)-1a, preferably, any one of q and s is 1 or more, andmore preferably, s is 1.

In Formula (II)-1a, preferably, X is an oxygen atom, k is 0, and any oneof q and s is 1 or more, and more preferably, X is an oxygen atom, k is0, and s is 1.

[1-16-1-b] The compound of Formula (II) or Formula (II)-1 according toAspect [1-16-1] is preferably a compound of Formula (II)-1b:

(where p, j, k, X, R¹, R^(2a), R^(2b), R³, R⁴, R⁵, and R⁶ are the sameas defined in Formula (I) described in Aspect [1]; the ring B′ is thesame as defined in Formula (B)-1 described in Aspect [1-14-a-1]; and q,r, s, the ring A″, V, R⁸, R⁹, and R¹⁰ are the same as defined in Formula(A) or Formula (A)-1 described in Aspect [1-13-c]), or a salt of thecompound, or a solvate of the compound or the salt.

More specifically, the preferable aspects of p, q, r, s, j, k, the ringA″, the ring B′, X, V, R¹, R^(2a), R^(2b), R³, R⁴, R⁵, R⁶, R⁸, R⁹, andR¹⁰ are the same as the preferable aspects described in any one ofAspects [1-1] to [1-15] and subordinate Aspects thereof. The preferableaspects of the partial structure of Formula (II)-1b corresponding toPartial Structural Formula (A)-1, Partial Structural Formula (B)-1,Partial Structural Formula (B-Het)-1b, or Partial Structural Formula (C)described in any one of Aspects [1-13-c], [1-14], and [1-15], andsubordinate Aspects thereof are the same as described in any one ofAspects [1-13-c], [1-14], and [1-15], and subordinate Aspects thereof.

In Formula (II)-1b, X is preferably an oxygen atom or —NH—, morepreferably an oxygen atom. In Formula (II)-1b, j is preferably 1. k ispreferably 0. In Formula (II)-1b, more preferably, X is an oxygen atomand k is 0. Further preferably, X is an oxygen atom, j is 1, and k is 0.

In Formula (II)-1b, in the ring B′, the linker moiety containing X andthe cyclic amide structure are preferably at the p-position. The ring B′is preferably a benzene ring.

In Formula (II)-1b, preferably, any one of q and s is 1 or more, andmore preferably, is 1.

In Formula (II)-1b, preferably, X is an oxygen atom, k is 0, and any oneof q and s is 1 or more, and more preferably, X is an oxygen atom, k is0, and s is 1.

[1-16-1-c] The compound of Formula (II) or Formula (II)-1 according toAspect [1-16-1] is preferably a compound of Formula (II)-1c:

(where p, j, k, X, R¹, R^(2a), R^(2b), R³, R⁴, R⁵, R⁶, R^(11a), R^(12a),and R^(12b) are the same as defined in Formula (I); the ring B′ is thesame as defined in Formula (B)-1 described in Aspect [1-14-a-1]; and q,r, s, the ring A″, V, R⁸, R⁹, and R¹⁰ are the same as defined in Formula(A) or Formula (A)-1 described in Aspect [1-13-c]), a salt of thecompound, or a solvate of the compound or the salt.

More specifically, the preferable aspects of p, q, r, s, j, k, the ringA″, the ring B′, X, V, R¹, R^(2a), R^(2b), R³, R⁴, R⁵, R⁶, R⁸, R⁹, R¹⁰,R^(11a), R^(12a), and R^(12b) are the same as the preferable aspectsdescribed in any one of Aspects [1-1] to [1-15] and subordinate Aspectsthereof. The preferable aspects of the partial structure of Formula(II)-1c corresponding to Partial Structural Formula (A)-1, PartialStructural Formula (B)-1, Partial Structural Formula (B-Het)-1c, orPartial Structural Formula (C) described in any one of Aspects [1-13-c],[1-14], and [1-15], and subordinate Aspects thereof are the same asdescribed in any one of Aspects [1-13-c], [1-14], and [1-15], andsubordinate Aspects thereof.

In Formula (II)-1c, X is preferably an oxygen atom or —NH—, morepreferably an oxygen atom. In Formula (II)-1c, j is preferably 1. k ispreferably 0. In Formula (II)-1c, more preferably, x is an oxygen atomand k is 0. Further preferably, X is an oxygen atom, j is 1, and k is 0.

In Formula (II)-1c, in the ring B′, the linker moiety containing X andthe cyclic amide structure are preferably at the p-position. The ring B′is preferably a benzene ring.

In Formula (II)-1c, preferably, any one of q and s is 1 or more, andmore preferably, is 1.

In Formula (II)-1c, preferably, X is an oxygen atom, k is 0, and any oneof q and s is 1 or more, and more preferably, X is an oxygen atom, k is0, and s is 1.

[1-16-1-d] The compound of Formula (II) or Formula (II)-1 according toAspect [1-16-1] is preferably a compound of Formula (II)-1d:

(where p, j, k, X, R¹, R^(2a), R^(2b), R³, R⁴, R⁵, R⁶, R^(11a), andR^(12c) are the same as defined in Formula (I); the ring B′ is the sameas defined in Formula (B)-1 described in Aspect [1-14-a-1]; and q, r, s,the ring A″, V, R⁸, R⁹, and R¹⁰ are the same as defined in Formula (A)or Formula (A)-1 described in Aspect [1-13-c]), a salt of the compound,or a solvate of the compound or the salt.

More specifically, the preferable aspects of p, q, r, s, j, k, the ringA″, the ring B′, X, V, R¹, R^(2a), R^(2b), R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹,R¹⁰, R^(11a), and R^(12c) are the same as the preferable aspectsdescribed in any one of Aspects [1-1] to [1-15] and subordinate Aspectsthereof. The preferable aspects of the partial structure of Formula(II)-1d corresponding to Partial Structural Formula (A)-1, PartialStructural Formula (B)-1, Partial Structural Formula (B-Het)-1d, orPartial Structural Formula (C) described in any one of Aspects [1-13-c],[1-14], and [1-15], and subordinate Aspects thereof are the same asdescribed in any one of Aspects [1-13-c], [1-14], and [1-15], andsubordinate Aspects thereof.

In Formula (II)-1d, X is preferably an oxygen atom or —NH—, morepreferably an oxygen atom. In Formula (II)-1d, j is preferably 1. k ispreferably 0. In Formula (II)-1d, more preferably, x is an oxygen atomand k is 0. Further preferably, X is an oxygen atom, j is 1, and k is 0.

In Formula (II)-1d, in the ring B′, the linker moiety containing X andthe cyclic amide structure are preferably at the p-position. The ring B′is preferably a benzene ring.

In Formula (II)-1d, preferably, any one of q and s is 1 or more, andmore preferably, s is 1.

In Formula (II)-1d, preferably, x is an oxygen atom, k is 0, and any oneof q and s is 1 or more, and more preferably, X is an oxygen atom, k is0, and s is 1.

[1-16-1-e] The compound of Formula (II) or Formula (II)-1 according toAspect [1-16-1] is preferably a compound of Formula (II)-1e:

(where p, j, k, X, R¹, R^(2a), R^(2b), R³, R⁴, R⁵, R⁶, R^(11a), andR^(12c) are the same as defined in Formula (I); the ring B′ is the sameas defined in Formula (B)-1 described in Aspect [1-14-a-1]; q, r, s, thering A″, V, R⁸, R⁹, and R¹⁰ are the same as defined in Formula (A) orFormula (A)-1 described in Aspect [1-13-c]; and h1 is the same asdefined in Formula (B-Het)-1e described in Aspect [1-14-d]), a salt ofthe compound, or a solvate of the compound or the salt.

More specifically, the preferable aspects of p, q, r, s, j, k, the ringA″, the ring B′, X, V, R¹, R^(2a), R^(2b), R³, R⁴, R⁵, R⁶, R⁸, R⁹, R¹⁰,R^(11a), R^(12c), and h1 are the same as the preferable aspectsdescribed in any one of Aspects [1-1] to [1-15] and subordinate Aspectsthereof. The preferable aspects of the partial structure of Formula(II)-1e corresponding to Partial Structural Formula (A)-1, PartialStructural Formula (B)-1, Partial Structural Formula (B-Het)-1e, orPartial Structural Formula (C) described in any one of Aspects [1-13-c],[1-14], and [1-15], and subordinate Aspects thereof are the same asdescribed in any one of Aspects [1-13-c], [1-14], and [1-15], andsubordinate Aspects thereof.

[1-16-1-f] The compound of Formula (II) or Formula (II)-1 according toAspect [1-16-1] is preferably a compound of Formula (II)-1f:

(where p, j, k, X, R¹, R^(2a), R^(2b), R³, R⁴, R⁵, R⁶, R^(11a), R^(12a),and R^(12b) are the same as defined in Formula (I); the ring B′ is thesame as defined in Formula (B)-1 described in Aspect [1-14-a-1]; q, r,s, the ring A″, V, R⁸, R⁹, and R¹⁰ are the same as defined in Formula(A) or Formula (A)-1 described in Aspect [1-13-c]; and h1 is the same asdefined in Formula (B-Het)-1f described in Aspect [1-14-d]), a salt ofthe compound, or a solvate of the compound or the salt.

More specifically, the preferable aspects of p, q, r, s, j, k, the ringA″, the ring B′, X, V, R¹, R^(2a), R^(2b), R³, R⁴, R⁵, R⁶, R⁸, R⁹, R¹⁰,R^(11a), R^(12a), R^(12b), and h1 are the same as the preferable aspectsdescribed in any one of Aspects [1-1] to [1-15] and subordinate

Aspects thereof. The preferable aspects of the partial structure ofFormula (II)-1f corresponding to Partial Structural Formula (A)-1,Partial Structural Formula (B)-1, Partial Structural Formula (B-Het)-1f,or Partial Structural Formula (C) described in any one of Aspects[1-13-c], [1-14], and [1-15], and subordinate Aspects thereof are thesame as described in any one of Aspects [1-13-c], [1-14], and [1-15],and subordinate Aspects thereof.

[1-16-1-1] The compound of Formula (II) or Formula (II)-1 according toAspect [1-16-1] is preferably Formula (II-1)-1:

(where n, p, h, J₂, R¹, R^(2a), and R^(2b) are the same as defined inFormula (I); the ring B′ and J_(1a) are the same as defined in Formula(B)-1 described in Aspect [1-14-a-1]; q, r, s, the ring A″, R⁸, R⁹, andR¹⁰ are the same as defined in Formula (A) or Formula (A)-1 described inAspect [1-13-c]; the broken lines are the same as defined in Formula(A1)-1 described in Aspect [1-13-c-1]; and E is a group optionallyselected from Formula (c1) to Formula (c6) shown as specific examples ofFormula (C) described in Aspect [1-15]).

More specifically, the preferable aspects of n, p, q, r, s, h, the ringA″, the ring B′, J_(1a), J₂, R¹, R^(2a), R^(2b), R⁸, R⁹, R¹⁰, the brokenlines, and E are the same as the preferable aspects described in any oneof Aspects [1-1] to [1-15] and subordinate Aspects thereof. Thepreferable aspects of the partial structure of Formula (II-1)-1corresponding to Partial Structural Formula (A1)-1 or Partial StructuralFormula (B1) described in any one of Aspects [1-13-c-1] and [1-14-a-2]are the same as described in any one of Aspects [1-13-c] and [1-14], andsubordinate Aspects thereof.

In Formula (II-1)-1, E is preferably Formula (c2) or Formula (c5), morepreferably Formula (c2).

In Formula (II-1)-1, the ring B′ is preferably a benzene ring.

In Formula (II-1)-1, E and the ring A″ are preferably at the m-position.

In Formula (II-1)-1, preferably, any one of q and s is 1 or more, andmore preferably, is 1.

In Formula (II-1)-1, preferably, E is Formula (c2), any one of q and sis 1 or more, and more preferably, E is Formula (c2) and s is 1.

[1-16-1-1-a] The compound of Formula (II-1)-1 is more preferably

Formula (II-1)-1a:

(where n, p, R¹, R^(2a), R^(2b), and R^(11a) are the same as defined inFormula (I); the ring B′ is the same as defined in Formula (B)-1described in Aspect [1-14-a-1]; q, r, s, the ring A″, R⁸, R⁹, and R¹⁰are the same as defined in Formula (A) or Formula (A)-1 described inAspect [1-13-c]; the broken lines are the same as defined in Formula(A1)-1 described in Aspect [1-13-c-1]; and E is a group optionallyselected from Formula (c1) to Formula (c6) shown as specific examples ofFormula (C) described in Aspect [1-15]).

More specifically, the preferable aspects of n, p, q, r, s, the ring A″,the ring B′, R¹, R^(2a), R^(2b), R⁸, R⁹, R¹⁰, R^(11a), the broken lines,and E are the same as the preferable aspects described in any one ofAspects [1-1] to [1-15] and subordinate Aspects thereof. The preferableaspects of the partial structure of Formula (II-1)-1a corresponding toPartial Structural Formula (A1)-1, Partial Structural Formula (B1), orPartial Structural Formula (B-Het)-1a described in any one of Aspects[1-13-c-1] and [1-14], and subordinate Aspects thereof are the same asdescribed in any one of Aspects [1-13-c] and [1-14], and subordinateAspects thereof.

In Formula (II-1)-1a, E is preferably Formula (c2) or Formula (c5), morepreferably Formula (c2).

In Formula (II-1)-1a, the ring B′ is preferably a benzene ring.

In Formula (II-1)-1a, E and the ring A″ are preferably at them-position.

In Formula (II-1)-1a, preferably, any one of q and s is 1 or more, andmore preferably, s is 1.

In Formula (II-1)-1a, preferably, E is Formula (c2), any one of q and sis 1 or more, and more preferably, E is Formula (c2) and s is 1.

[1-16-1-1-b] The compound of Formula (II-1)-1 is more preferably Formula(II-1)-1b:

(where p, R¹, R^(2a), and R^(2b) are the same as defined in Formula (I);the ring B′ is the same as defined in Formula (B)-1 described in Aspect[1-14-a-1]; q, r, s, the ring A″, R⁸, R⁹, and R¹⁰ are the same asdefined in Formula (A) or Formula (A)-1 described in Aspect [1-13-c];the broken lines are the same as defined in Formula (A1)-1 described inAspect [1-13-c-1]; and E is a group optionally selected from Formula(c 1) to Formula (c6) shown as specific examples of Formula (C)described in Aspect [1-15]).

More specifically, the preferable aspects of p, q, r, s, the ring A″,the ring B′, R¹,R^(2a), R^(2b), R⁸, R⁹, R¹⁰, the broken lines, and E arethe same as the preferable aspects described in any one of Aspects [1-1]to [1-15] and subordinate Aspects thereof. The preferable aspects of thepartial structure of Formula (II-1)-1b corresponding to PartialStructural Formula (A1)-1, Partial Structural Formula (B1), or PartialStructural Formula (B-Het)-1b described in any one of Aspects [1-13-c-1]and [1-14], and subordinate Aspects thereof are the same as described inany one of Aspects [1-13-c] and [1-14], and subordinate Aspects thereof.

In Formula (II-1)-1b, E is preferably Formula (c2) or Formula (c5), morepreferably Formula (c2).

In Formula (II-1)-1b, the ring B′ is preferably a benzene ring.

In Formula (II-1)-1b, E and the ring A″ are preferably at them-position.

In Formula (II-1)-1b, preferably, any one of q and s is 1 or more, andmore preferably, s is 1.

In Formula (II-1)-1b, preferably, E is Formula (c2), any one of q and sis 1 or more, and more preferably, E is Formula (c2) and s is 1.

[1-16-1-1-c] The compound of Formula (II-1)-1 is more preferably Formula(II-1)-1c:

(where p, R¹, R^(2a), R^(2b), R^(11a), R^(12a), R^(12b) are the same asdefined in Formula (I); the ring B′ is the same as defined in Formula(B)-1 described in Aspect [1-14-a-1]; q, r, s, the ring A″, R⁸, R⁹, andR¹⁰ are the same as defined in Formula (A) or Formula (A)-1 described inAspect [1-13-c]; the broken lines are the same as defined in Formula(A1)-1 described in Aspect [1-13-c-1]; and E is a group optionallyselected from Formula (c1) to Formula (c6) shown as specific examples ofFormula (C) described in Aspect [1-15]).

More specifically, the preferable aspects of p, q, r, s, the ring A″,the ring B′, R¹, R^(2a), R^(2b), R⁸, R⁹, R¹⁰, R^(11a), R^(12a), R^(12b),the broken lines, and E are the same as the preferable aspects describedin any one of Aspects [1-1] to [1-15] and subordinate Aspects thereof.

The preferable aspects of the partial structure of Formula (II-1)-1ccorresponding to Partial Structural Formula (A1)-1, Partial StructuralFormula (B 1), or Partial Structural Formula (B-Het)-1c described in anyone of Aspects [1-13-c-1] and [1-14], and subordinate Aspects thereofare the same as described in any one of Aspects [1-13-c] and [1-14], andsubordinate Aspects thereof.

In Formula (II-1)-1c, E is preferably Formula (c2) or Formula (c5), morepreferably Formula (c2).

In Formula (II-1)-1c, the ring B′ is preferably a benzene ring.

In Formula (II-1)-1c, E and the ring A″ are preferably at them-position.

In Formula (II-1)-1c, preferably, any one of q and s is 1 or more, andmore preferably, s is 1.

In Formula (II-1)-1c, preferably, E is Formula (c2), any one of q and sis 1 or more, and more preferably, E is Formula (c2) and s is 1.

[1-16-1-1-d] The compound of Formula (II-1)-1 is more preferably Formula(II-1)-1d:

(where p, R¹, R^(2a), R^(2b), R^(11a), and R^(12c) are the same asdefined in Formula (I); the ring B′ is the same as defined in Formula(B)-1 described in Aspect [1-14-a-1]; q, r, s, the ring A″, R⁸, R⁹, andR¹⁰ are the same as defined in Formula (A) or Formula (A)-1 described inAspect [1-13-c]; the broken lines are the same as defined in Formula(A1)-1 described in Aspect [1-13-c-1]; and E is a group optionallyselected from Formula (c1) to Formula (c6) shown as specific examples ofFormula (C) described in Aspect [1-15]).

More specifically, the preferable aspects of p, q, r, s, the ring A″,the ring B′, R¹, R^(2a), R^(2b), R⁸, R⁹, R¹⁰, R^(11a), R^(12c), thebroken lines, and E are the same as the preferable aspects described inany one of Aspects [1-1] to [1-15] and subordinate Aspects thereof. Thepreferable aspects of the partial structure of Formula (II-1)-1dcorresponding to Partial Structural Formula (A1)-1, Partial StructuralFormula (B 1), or Partial Structural Formula (B-Het)-1d described in anyone of Aspects [1-13-c-1] and [1-14], and subordinate Aspects thereofare the same as described in any one of Aspects [1-13-c] and [1-14], andsubordinate Aspects thereof.

In Formula (II-1)-1d, E is preferably Formula (c2) or Formula (c5), morepreferably Formula (c2).

In Formula (II-1)-1d, the ring B′ is preferably a benzene ring.

In Formula (II-1)-1d, E and the ring A″ are preferably at them-position.

In Formula (II-1)-1d, preferably, any one of q and s is 1 or more, andmore preferably, s is 1.

In Formula (II-1)-1d, preferably, E is Formula (c2), any one of q and sis 1 or more, and more preferably, E is Formula (c2) and s is 1.

[1-16-1-1-e] The compound of Formula (II-1)-1 is more preferably Formula(II-1)-1e:

(where p, R¹, R^(2a), R^(2b), R^(11a), and R^(12c) are the same asdefined in Formula (I); the ring B′ is the same as defined in Formula(B)-1 described in Aspect [1-14-a-1]; q, r, s, the ring A″, R⁸, R⁹, andR¹⁰ are the same as defined in Formula (A) or Formula (A)-1 described inAspect [1-13-c]; h1 is the same as defined in Formula (B-Het)-1edescribed in Aspect [1-14-d]; the broken lines are the same as definedin Formula (A1)-1 described in Aspect [1-13-c-1]; and E is a groupoptionally selected from Formula (c1) to Formula (c6) shown as specificexamples of Formula (C) described in Aspect [1-15]).

More specifically, preferable aspects of p, q, r, s, the ring A″, thering B′, R¹, R^(2a), R^(2b), R⁸, R⁹, R¹⁰, R^(11a), R^(12c), h1, thebroken lines, and E are the same as the preferable aspects described inany one of Aspects [1-1] to [1-15] and subordinate Aspects thereof.Preferable aspects of the partial structure of Formula (II-1)-1ecorresponding to Partial Structural Formula (A1)-1, Partial StructuralFormula (B1), or Partial Structural Formula (B-Het)-1e described in anyone of Aspects [1-13-c-1] and [1-14], and subordinate Aspects thereofare the same as described in any one of Aspects [1-13-c] and [1-14], andsubordinate Aspects thereof.

[1-16-1-1-f] The compound of Formula (II-1)-1 is more preferably Formula(II-1)-1f:

(where p, R¹, R^(2a), R^(2b), R^(11a), R^(12a), and R^(12b) are the sameas defined in Formula (I); the ring B′ is the same as defined in Formula(B)-1 described in Aspect [1-14-a-1]; q, r, s, the ring A″, R⁸, R⁹, andR¹⁰ are the same as defined in Formula (A) or Formula (A)-1 described inAspect [1-13-c]; h1 is the same as defined in Formula (B-Het)-1fdescribed in Aspect [1-14-d]; the broken lines are the same as definedin Formula (A1)-1 described in Aspect [1-13-c-1]; and E is a groupoptionally selected from Formula (c1) to Formula (c6) shown as specificexamples of Formula (C) described in Aspect [1-15]).

More specifically, preferable aspects of p, q, r, s, the ring A″, thering B′, R¹, R^(2a), R^(2b), R⁸, R⁹, R¹⁰, R^(11a), R^(12a), R^(12b), h1,the broken lines, and E are the same as the preferable aspects describedin any one of Aspects [1-1] to [1-15] and subordinate Aspects thereof.Preferable aspects of the partial structure of Formula (II-1)-1fcorresponding to Partial Structural Formula (A1)-1, Partial StructuralFormula (B1), or Partial Structural Formula (B-Het)-1f described in anyone of Aspects [1-13-c-1] and [1-14], and subordinate Aspects thereofare the same as described in any one of Aspects [1-13-c] and [1-14], andsubordinate Aspects thereof.

[1-16-1-2] The compound of Formula (II-1)-1 according to Aspect[1-16-1-1] is more preferably Formula (II-1-A):

(where n, p, h, J₂, R¹, R^(2a), and R^(2b) are the same as defined inFormula (I); J_(1a) is the same as defined in Formula (B)-1 described inAspect [1-14-a-1]; q, r, R⁸, R⁹, and R¹⁰ are the same as defined inFormula (A) described in Aspect [1-13-c]; and G₂ is the same as definedin Formula (A1a) described in Aspect [1-13-c-3-1]).

More specifically, preferable aspects of n, p, q, r, h, J_(1a), R¹,R^(2a), R^(2b), R⁸, R⁹, R¹⁰, and G₂ are the same as the preferableaspects described in any one of Aspects [1-1] to [1-15] and subordinateAspects thereof. Preferable aspects of the partial structure of Formula(II-1-A) corresponding to Partial Structural Formula (A1a) or PartialStructural Formula (B1a) described in Aspect [1-13-c-3-1] or [1-14-a-4]are the same as described in any one of Aspects [1-13-c] and [1-14], andsubordinate Aspects thereof.

[1-16-1-2a] In Formula (II-1-A), preferably, r is 0 or 1 and R¹⁰ is aC₁₋₄ alkyl group. Preferably, q is an integer of 1 to 3 and R⁹ is ahalogen atom or a C₁₋₄ alkyl group. R⁸ is preferably a C₁₋₆ alkoxy group(the alkoxy group is substituted with 1 to 5—OH, 1 to 5 ethoxy, 1 to 5methylsulfonyl, 1 to 5 sulfamoyl, 1 to 5 methylsulfamoyl, 1 to 5dimethylsulfamoyl, 1 to 5 carbamoyl, 1 to 5 methylcarbamoyl, 1 to 5dimethylcarbamoyl, 1 to 5—NH₂, 1 to 5 acetylamino, 1 to 5methylsulfonylamino, 1 to 5 2-oxo-1-pyrrolidinyl, or 1 to 53-methyloxetane-3-yl) or (1,1-dioxidetetrahydro-2H-thiopyran-4-yl)oxy.More preferably, R⁸ is a C₁₋₆ alkoxy group (the alkoxy group issubstituted with 1 to 5 —OH, 1 to 5 ethoxy, 1 to 5 methylsulfonyl, 1 to5—NH₂, 1 to 5 acetylamino, 1 to 5 methylsulfonylamino, 1 to 52-oxo-1-pyrrolidinyl, or 1 to 5 3-methyloxetane-3-yl) or(1,1-dioxidetetrahydro-2H-thiopyran-4-yl)oxy. Further preferably, R⁸ isa C₁₋₆ alkoxy group (the alkoxy group is substituted with 1 to 2 —OH, 1to 2 ethoxy, 1 to 2 methylsulfonyl, or 1 to 2—NH₂).

[1-16-1-2-a] The compound of Formula (II-1-A) according to Aspect[1-16-1-2] is more preferably Formula (II-1-A)-a:

(where n, p, R¹, R^(2a), R^(2b), and R^(11a) are the same as defined inFormula (I); q, r, R⁸, R⁹, and R¹⁰ are the same as defined in Formula(A) described in Aspect [1-13-c]; and G₂ is the same as defined inFormula (A1a) described in Aspect [1-13-c-3-1]).

More specifically, preferable aspects of n, p, q, r, R¹, R^(2a), R^(2b),R⁸, R⁹, R¹⁰, R¹¹, R^(11a) and G₂ are the same as the preferable aspectsdescribed in any one of Aspects [1-1] to [1-15] and subordinate Aspectsthereof. Preferable aspects of the partial structure of Formula(II-1-A)-a corresponding to Partial Structural Formula (A1a), PartialStructural Formula (B1a), or Partial Structural Formula (B-Het)-1adescribed in any one of Aspects [1-13-c-3-1] and [1-14], and subordinateAspects thereof are the same as described in any one of Aspects [1-13-c]and [1-14], and subordinate Aspects thereof. Preferable aspects of q, r,R⁸, R⁹, and R¹⁰ are the same as described in Aspect [1-16-1-2a].

[1-16-1-2-b] The compound of Formula (II-1-A) according to Aspect[1-16-1-2] is more preferably Formula (II-1-A)-b:

(where p, R¹, R^(2a), and R^(2b) are the same as defined in Formula (I);q, r, R⁸, R⁹, and R¹⁰ are the same as defined in Formula (A) describedin Aspect [1-13-c]; and G₂ is the same as defined in Formula (A1a)described in Aspect [1-13-c-3-1]).

More specifically, preferable aspects of p, q, r, R¹, R^(2a), R^(2b),R⁸, R⁹, R¹⁰, and G₂ are the same as the preferable aspects described inany one of Aspects [1-1] to [1-15] and subordinate Aspects thereof.Preferable aspects of the partial structure of Formula (II-1-A)-bcorresponding to Partial Structural Formula (A1a), Partial StructuralFormula (B1a), or Partial Structural Formula (B-Het)-1b described in anyone of Aspects [1-13-c-3-1] and [1-14], and subordinate Aspects thereofare the same as described in any one of Aspects [1-13-c] and [1-14], andsubordinate Aspects thereof. Preferable aspects of q, r, R⁸, R⁹, and R¹⁰are the same as described in Aspect [1-16-1-2a].

[1-16-1-2-c] The compound of Formula (II-1-A) according to Aspect[1-16-1-2] is more preferably Formula (II-1-A)-c:

(where p, R¹, R^(2a), R^(2b), R^(11a), R^(12a), and R^(12b) are the sameas defined in Formula (I); q, r, R⁸, R⁹, and R¹⁰ are the same as definedin Formula (A) described in Aspect [1-13-c]; and G₂ is the same asdefined in Formula (A1a) described in Aspect [1-13-c-3-1]).

More specifically, preferable aspects of p, q, r, R¹, R^(2a), R^(2b),R⁸, R⁹, R¹⁰, R^(11a), R^(12a), R^(12b), and G₂ are the same as thepreferable aspects described in any one of Aspects [1-1] to [1-15] andsubordinate Aspects thereof. Preferable aspects of the partial structureof Formula (II-1-A)-c corresponding to Partial Structural Formula (A1a),Partial Structural Formula (B1a), or Partial Structural Formula(B-Het)-1c described in any one of Aspects [1-13-c-3-1] and [1-14], andsubordinate Aspects thereof are the same as described in any one ofAspects [1-13-c] and [1-14], and subordinate Aspects thereof. Preferableaspects of q, r, R⁸, R⁹, and R¹⁰ are the same as described in Aspect[1-16-1-2a].

[1-16-1-2-d] The compound of Formula (II-1-A) according to Aspect[1-16-1-2] is more preferably Formula (II-1-A)-d:

(where p, R¹, R^(2a), R^(2b), R^(11a), and R^(12c) are the same asdefined in Formula (I); q, r, R⁸, R⁹, and R¹⁰ are the same as defined inFormula (A) described in Aspect [1-13-c]; and G₂ is the same as definedin Formula (A1a) described in Aspect [1-13-c-3-1]).

More specifically, preferable aspects of p, q, r, R¹, R^(2a), R^(2b),R⁸, R⁹, R¹⁰, R¹¹, R^(12c), and G₂ are the same as the preferable aspectsdescribed in any one of Aspects [1-1] to [1-15] and subordinate Aspectsthereof. Preferable aspects of the partial structure of Formula(II-A-1)-d corresponding to Partial Structural Formula (A1a), PartialStructural Formula (B1a), or Partial Structural Formula (B-Het)-1ddescribed in any one of Aspects [1-13-c-3-1] and [1-14], and subordinateAspects thereof are the same as described in any one of Aspects [1-13-c]and [1-14], and subordinate Aspects thereof. Preferable aspects of q, r,R⁸, R⁹, and R¹⁰ are the same as described in Aspect [1-16-1-2a].

[1-16-1-2-e] The compound of Formula (II-1-A) according to Aspect[1-16-1-2] is more preferably Formula (II-1-A)-e:

(where p, R¹, R^(2a), R^(2b), R^(11a), and R^(12c) are the same asdefined in Formula (I); q, r, R⁸, R⁹, and R¹⁰ are the same as defined inFormula (A) described in Aspect [1-13-c]; h1 is the same as defined inFormula (B-Het)-1e described in Aspect [1-14-d]; and G₂ is the same asdefined in Formula (A1a) described in Aspect [1-13-c-3-1]).

More specifically, preferable aspects of p, q, r, R¹, R^(2a), R^(2b),R⁸, R⁹, R¹⁰, R^(11a), R^(12c), h1, and G₂ are the same as the preferableaspects described in any one of Aspects [1-1] to [1-15] and subordinateAspects thereof. Preferable aspects of the partial structure of Formula(II-1-A)-e corresponding to Partial Structural Formula (A1a), PartialStructural Formula (B1a), or Partial Structural Formula (B-Het)-1edescribed in any one of Aspects [1-13-c-3-1] and [1-14], and subordinateAspects thereof are the same as described in any one of Aspects [1-13-c]and [1-14], and subordinate Aspects thereof. Preferable aspects of q, r,R⁸, R⁹, and R¹⁰ are the same as described in Aspect [1-16-1-2a].

[1-16-1-2-f] The compound of Formula (II-1-A) according to Aspect[1-16-1-2] is more preferably Formula (II-1-A)-f:

(where p, R¹, R^(2a), R^(2b), R^(11a), R^(12a), and R^(12b) are the sameas defined in Formula (I); q, r, R⁸, R⁹, and R¹⁰ are the same as definedin Formula (A) described in Aspect [1-13-c]; h1 is the same as definedin Formula (B-Het)-1f described in Aspect [1-14-d]; and G₂ is the sameas defined in Formula (A1a) described in Aspect [1-13-c-3-1]).

More specifically, preferable aspects of p, q, r, R¹, R^(2a), R^(2b),R⁸, R⁹, R¹⁰, R^(11a), R^(12a), R^(12b), h1, and G₂ are the same as thepreferable aspects described in any one of Aspects [1-1] to [1-15] andsubordinate Aspects thereof. Preferable aspects of the partial structureof Formula (II-1-A)-f corresponding to Partial Structural Formula (A1a),Partial Structural Formula (B1a), or Partial Structural Formula(B-Het)-1f described in any one of Aspects [1-13-c-3-1] and [1-14], andsubordinate Aspects thereof are the same as described in any one ofAspects [1-13-c] and [1-14], and subordinate Aspects thereof. Preferableaspects of q, r, R⁸, R⁹, and R¹⁰ are the same as described in Aspect[1-16-1-2a].

[1-16-1-3] The compound of Formula (II-1)-1 according to Aspect[1-16-1-1] is more preferably Formula (II-1-B):

(where n, p, h, J₂, R¹, R^(2a), and R^(2b) are the same as defined inFormula (I); J_(1a) is the same as defined in Formula (B)-1 described inAspect [1-14-a-1]; q, r, R⁹, and R¹⁰ are the same as defined in Formula(A) described in Aspect [1-13-c]; and G₂ is the same as defined inFormula (A1a) described in Aspect [1-13-c-3-1]).

Specifically, preferable aspects of n, p, q, r, h, J_(1a), J₂, R¹,R^(2a), R^(2b), R⁹, R¹⁰, and G₂ are the same as the preferable aspectsdescribed in any one of Aspects [1-1] to [1-15] and subordinate Aspectsthereof. Preferable aspects of the partial structure of Formula (II-1-B)corresponding to Partial Structural Formula (A1c) or Partial StructuralFormula (B1a) described in Aspect [1-13-c-3-1] or [1-14-a-4] are thesame as described in any one of Aspects [1-13-c] and [1-14], andsubordinate Aspects thereof.

[1-16-1-3a] In Formula (II-1-B), preferably, r is 0 or 1 and R¹⁰ is aC₁₋₄ alkyl group. Preferably, q is an integer of 1 to 3 and R⁹ is ahalogen atom or a C₁₋₄ alkyl group.

[1-16-1-3-a] The compound of Formula (II-1-B) according to Aspect[1-16-1-3] is more preferably Formula (II-1-B)-a:

(where n, p, R¹, R^(2a), R^(2b), and R^(11a) are the same as defined inFormula (I); q, r, R⁹, and R¹⁰ are the same as defined in Formula (A)described in Aspect [1-13-c]; and G₂ is the same as defined in Formula(A1a) described in Aspect [1-13-c-3-1]).

More specifically, preferable aspects of n, p, q, r, R¹, R^(2a), R^(2b),R⁹, R¹⁰, R^(11a), and G₂ are the same as the preferable aspectsdescribed in any one of Aspects [1-1] to [1-15] and subordinate Aspectsthereof. Preferable aspects of the partial structure of Formula(II-1-B)-a corresponding to Partial Structural Formula (A1c), PartialStructural Formula (B1a), or Partial Structural Formula (B-Het)-1adescribed in any one of Aspects [1-13-c-3-1] and [1-14], and subordinateAspects thereof are the same as described in any one of Aspects [1-13-c]and [1-14], and subordinate Aspects thereof. Preferable aspects of q, r,R⁹, and R¹⁰ are the same as described in Aspect [1-16-1-3a].

[1-16-1-3-b] The compound of Formula (II-1-B) according to Aspect[1-16-1-3] is more preferably Formula (II-1-B)-b:

(where p, R¹, R^(2a), and R^(2b) are the same as defined in Formula (I);q, r, R⁹, and R¹⁰ are the same as defined in Formula (A) described inAspect [1-13-c]; and G₂ is the same as defined in Formula (A1a)described in Aspect [1-13-c-3-1]).

More specifically, preferable aspects of p, q, r, R¹, R^(2a), R^(2b),R⁹, R¹⁰ and G₂ are the same as the preferable aspects described in anyone of Aspects [1-1] to [1-15] and subordinate Aspects thereof.Preferable aspects of the partial structure of Formula (II-1-B)-bcorresponding to Partial Structural Formula (A1c), Partial StructuralFormula (B1a), or Partial Structural Formula (B-Het)-1b described in anyone of Aspects [1-13-c-3-1] and [1-14], and subordinate Aspects thereofare the same as described in any one of Aspects [1-13-c] and [1-14], andsubordinate Aspects thereof. Preferable aspects of q, r, R⁹, and R¹⁰ arethe same as described in Aspect [1-16-1-3a].

[1-16-1-3-c] The compound of Formula (II-1-B) according to Aspect[1-16-1-3] is more preferably Formula (II-1-B)-c:

(where p, R¹, R^(2a), R^(2b), R^(11a), R^(12a), and R^(12b) are the sameas defined in Formula (I); q, r, R⁹, and R¹⁰ are the same as defined inFormula (A) described in Aspect [1-13-c]; and G₂ is the same as definedin Formula (A1a) described in Aspect [1-13-c-3-1]).

More specifically, preferable aspects of p, q, r, R¹, R^(2a), R^(2b),R⁹, R¹⁰, R^(11a), R^(12a), R^(12b), and G₂ are the same as thepreferable aspects described in any one of Aspects [1-1] to [1-15] andsubordinate Aspects thereof. Preferable aspects of the partial structureof Formula (II-1-B)-c corresponding to Partial Structural Formula (A1c),Partial Structural Formula (B1a), or Partial Structural Formula(B-Het)-1c described in any one of Aspects [1-13-c-3-1] and [1-14], andsubordinate Aspects thereof are the same as described in any one ofAspects [1-13-c] and [1-14], and subordinate Aspects thereof. Preferableaspects of q, r, R⁹, and R¹⁰ are the same as described in Aspect[1-16-1-3a].

[1-16-1-3-d] The compound of Formula (II-1-B) according to Aspect[1-16-1-3] is more preferably Formula (II-1-B)-d:

(where p, R¹, R^(2a), R^(11a), and R^(12c) are the same as defined inFormula (I); q, r, R⁹, and R¹⁰ are the same as defined in Formula (A)described in Aspect [1-13-c]; and G₂ is the same as defined in Formula(A1a) described in Aspect [1-13-c-3-1]).

More specifically, preferable aspects of p, q, r, R¹, R^(2a), R^(2b),R⁹, R¹⁰, R^(11a), R^(12c), and G₂ are the same as the preferable aspectsdescribed in any one of Aspects [1-1] to [1-15] and subordinate Aspectsthereof. Preferable aspects of the partial structure of Formula(II-1-B)-d corresponding to Partial Structural Formula (A1c), PartialStructural Formula (B1a), or Partial Structural Formula (B-Het)-1ddescribed in any one of Aspects [1-13-c-3-1] and [1-14], and subordinateAspects thereof are the same as described in any one of Aspects [1-13-c]and [1-14], and subordinate Aspects thereof. Preferable aspects of q, r,R⁹, and R¹⁰ are the same as described in Aspect [1-16-1-3a].

[1-16-1-3-e] The compound of Formula (II-1-B) according to Aspect[1-16-1-3] is more preferably Formula (II-1-B)-e:

(where p, R¹, R^(2a), R^(2b), R11 a, and R^(12c) are the same as definedin Formula (I); q, r, R⁹, and R¹⁰ are the same as defined in Formula (A)described in Aspect [1-13-c]; h1 is the same as defined in Formula(B-Het)-1e described in Aspect [1-14-d]; and G₂ is the same as definedin Formula (A1a) described in Aspect [1-13-c-3-1]).

More specifically, preferable aspects of p, q, r, R¹, R^(2a), R^(2b),R⁹, R¹⁰, R^(11a), R^(12c), h1, and G₂ are the same as the preferableaspects described in any one of Aspects [1-1] to [1-15] and subordinateAspects thereof. Preferable aspects of the partial structure of Formula(II-1-B)-e corresponding to Partial Structural Formula (A1c), PartialStructural Formula (B1a), or Partial Structural Formula (B-Het)-1edescribed in any one of Aspects [1-13-c-3-1] and [1-14], and subordinateAspects thereof are the same as described in any one of Aspects [1-13-c]and [1-14], and subordinate Aspects thereof. Preferable aspects of q, r,R⁹, and R¹⁰ are the same as described in Aspect [1-16-1-3a].

[1-16-1-34] The compound of Formula (II-1-B) according to Aspect[1-16-1-3] is more preferably Formula (II-1-B)-f:

(where p, R¹, R^(2a), R^(2b), R^(11a), R^(12a), and R^(12b) are the sameas defined in Formula (I); q, r, R⁹, and R¹⁰ are the same as defined inFormula (A) described in Aspect [1-13-c]; h1 is the same as defined inFormula (B-Het)-1f described in Aspect [1-14-d]; and G₂ is the same asdefined in Formula (A1a) described in Aspect [1-13-c-3-1]).

More specifically, preferable aspects of p, q, r, R¹, R^(2a), R^(2b),R⁹, R¹⁰, R^(11a), R^(12a), R^(12b), h1, and G₂ are the same as thepreferable aspects described in any one of Aspects [1-1] to [1-15] andsubordinate Aspects thereof. Preferable aspects of the partial structureof Formula (II-1-B)-f corresponding to Partial Structural Formula (A1c),Partial Structural Formula (B1a), or Partial Structural Formula(B-Het)-1f described in any one of Aspects [1-13-c-3-1] and [1-14], andsubordinate Aspects thereof are the same as described in any one ofAspects [1-13-c] and [1-14], and subordinate Aspects thereof. Preferableaspects of q, r, R⁹, and R¹⁰ are the same as described in Aspect[1-16-1-3a].

[1-16-1-4] As the compound of Formula (I) according to Aspect [1] or ofFormula (II) or Formula (II)-1 according to Aspect [1-16-1], apreferable compound is Formula (II-B):

(where n, p, h, J₂, R¹, R^(2a), and R^(2b) are the same as defined inFormula (I) described in Aspect [1]; J_(1a) is the same as defined inFormula (B)-1 described in Aspect [1-14-a-1]; and W, Y, Z, R^(9c),R^(9d), R^(10a1), R^(10a2), R^(10a3), R^(10b), R^(10c), and R^(10d), arethe same as defined in Formula (A1)-1-1 or Formula (R^(10a′)) describedin Aspect [1-13-c-11]).

More specifically, preferable aspects of n, p, h, J_(1a), J₂, R¹,R^(2a), R^(2b), W, Y, Z, R^(9c), R^(9d), R^(10a1), R^(10a2), R^(10a3),R^(10b), R^(10c), and R^(10d) are the same as the preferable aspectsdescribed in any one of Aspects [1-1] to [1-15] and subordinate Aspectsthereof.

[1-16-1-5] As the compound of Formula (I) according to Aspect [1] or ofFormula (II) or Formula (II)-1 according to Aspect [1-16-1], apreferable compound is Formula (II-C):

(where n, p, h, J₂, R¹, R^(2a), and R^(2b) are the same as defined inFormula (I) described in Aspect [1]; J_(1a) is the same as defined inFormula (B)-1 described in Aspect [1-14-a-1]; and W, Y, Z, R^(9c),R^(9d), R^(10a), R^(10b), R^(10c), and R^(10d) are the same as definedin Formula (A1)-1-1 described in Aspect [1-13-c-11]).

More specifically, preferable aspects of n, p, h, J_(1a), J₂, R¹,R^(2a), R^(2b), W, Y, Z, R^(9c), R^(9d), R^(10a), R^(10b), R^(10c), andR^(10d) are the same as the preferable aspects described in any one ofAspects [1-1] to [1-15] and subordinate Aspects thereof.

[1-16-2] As the compound of Formula (I) according to Aspect [1], apreferable compound is a compound in which the ring A is Formula (AA),that is, a compound of Formula (III):

(where n, p, h, j, k, J₂, X, R¹, R^(2a), R^(2b), R³, R⁴, R⁵, and R⁶ arethe same as defined in Formula (I); the ring B′ and J_(1a) are the sameas defined in Formula (B)-1 described in Aspect [1-14-a-1]; and f, g,q1, q2, r1, the ring A′″, T, R¹³, R^(13a), and R¹⁴ are the same asdefined in Formula (AA) described in Aspect [1-13-d]), a salt of thecompound, or a solvate of the compound or the salt.

More specifically, preferable aspects of n, p, h, j, k, f, g, q1, q2,r1, the ring A′″, the ring B′, J_(1a), J₂, T, X, R¹, R^(2a), R^(2b), R³,R⁴, R⁵, R⁶, R¹³, R^(13a), and R¹⁴ are the same as described in any oneof Aspects [1-1] to [1-15] and the subordinate Aspects thereof.

In Formula (III), X is preferably an oxygen atom or —NH—, morepreferably an oxygen atom. In Formula (III), j is preferably 0 and k ispreferably 0. In Formula (III), more preferably, X is an oxygen atom, jis 0, and k is 0.

In Formula (III), the ring B′ is preferably a benzene ring.

In Formula (III), preferably, any one of q1 and q2 is 1 or more, morepreferably, q2 is 1.

In Formula (III), preferably, X is an oxygen atom, j is 0, k is 0, andany one of q1 and q2 is 1 or more, more preferably, X is an oxygen atom,j is 0, k is 0, and q2 is 1.

[1-16-2a] In the compound of Formula (III) according to Aspect [1-16-2],compounds produced by optionally combining the groups of PartialStructural Formula (AA) (on the left of the left wavy line), PartialStructural Formula (B)-1 (on the right of the right wavy line), andPartial Structural Formula (C) (between the two wavy lines) in Formula(III) can be produced optionally:

More specifically, Partial Structural Formula (AA) is a group optionallyselected from Formula (AA)-1, For (AA)-1-1, Formula (AA1), Formula(AA1)-1, Formula (AA1a)-1, Formula (AA1a)-1-1, Formula (AA1b), andFormula (AA1b)-1 described in Aspects [1-13-d-1] to [1-13-d-7-1].Partial Structural Formula (B) is a group optionally selected fromFormula (B 1), Formula (B2), Formula (B1a), and Formula (Bib) describedin Aspects [1-14-a-2] and [1-14-a-4], and Partial Structural Formula (C)can be a group optionally selected from Formula (c1) to Formula (c6)described in Aspect [1-15]. An optional combination of each formulaforms part of the compound of Formula (I) according to the presentinvention.

The cyclic amide structure bonded to the ring B′ of Formula (III) isPartial Structural Formula (B-Het)-1 described in Aspect [1-14-e], andpreferable examples of the cyclic amide structure include Formula(B-Het)-1a, (B-Het)-1b, Formula (B-Het)-1c, Formula (B-Het)-1d, Formula(B-Het)-1e, and Formula (B-Het)-1f described in Aspect [1-14-e-1]. InFormula (III), a compound having Formula (B-Het)-1a is Formula (III)-1a,a compound having Formula (B-Het)-1b is Formula (III)-1b, a compoundhaving Formula (B-Het)-1c is Formula (III)-1c, a compound having Formula(B-Het)-1d is Formula (III)-1d, a compound having Formula (B-Het)-1e isFormula (III)-1e, and a compound having Formula (B-Het)-1f is Formula(III)-1f.

[1-16-2-1] The compound of Formula (III) according to Aspect [1-16-2] ispreferably Formula (III-1):

(where n, p, h, J₂, R¹, R^(2a), and R^(2b) are the same as defined inFormula (I); the ring B′ and J_(1a) are the same as defined in Formula(B)-1 described in Aspect [1-14-a-1]; q1, q2, r1, T, R¹³, R^(13a), andR¹⁴ are the same as defined in Formula (AA) described in Aspect[1-13-d]; and E is a group optionally selected from Formula (c1) toFormula (c6) shown as specific examples of Formula (C) described inAspect [1-15]).

More specifically, preferable aspects of n, p, h, q1, q2, r1, the ringB′, T, J_(1a), J₂, R¹, R^(2a), R^(2b), R¹³, R^(13a), R¹⁴, and E are thesame as the preferable aspects described in any one of Aspects [1-1] to[1-15] and subordinate Aspects thereof.

In Formula (III-1), E is preferably Formula (c1) or Formula (c4), morepreferably Formula (c1).

In Formula (III-1), the ring B′ is preferably a benzene ring.

In Formula (III-1), preferably, any one of q1 and q2 is 1 or more, andmore preferably, q2 is 1.

In Formula (III-1), preferably, E is Formula (c1) and any one of q1 andq2 is 1 or more, more preferably, E is Formula (c1) and q2 is 1.

The cyclic amide structure bonded to the ring B′ of Formula (III-1) isPartial Structural Formula (B-Het)-1 described in Aspect [1-14-e], andpreferable examples of the cyclic amide structure include Formula(B-Het)-1a, (B-Het)-1b, Formula (B-Het)-1c, Formula (B-Het)-1d, Formula(B-Het)-1e, and Formula (B-Het)-1f described in Aspect [1-14-e-1]. InFormula (III-1), a compound having Formula (B-Het)-1a is Formula(III-1)-1a, a compound having Formula (B-Het)-1b is Formula (III-1)-1b,a compound having Formula (B-Het)-1c is Formula (III-1)-1c, a compoundhaving Formula (B-Het)-1d is Formula (III-1)-1d, a compound havingFormula (B-Het)-1e is Formula (III-1)-1e, and a compound having Formula(B-Het)-1f is Formula (III-1)-1f.

[1-16-2-2] The compound of Formula (III) according to Aspect [1-16-2] orof Formula (III-1) according to Aspect [16-2-1] is preferably Formula(III-1)-1:

(where n, p, h, J₂, R¹, R^(2a), and R^(2b) are the same as defined inFormula (I); J_(1a) is the same as defined in Formula (B)-1 described inAspect [1-14-a-1]; q, s, the ring A′, V, R⁸, and R⁹ are the same asdefined in Formula (A) described in Aspect [1-13-c]; q1, r1, T, R¹³, andR¹⁴ are the same as defined in Formula (AA) described in Aspect[1-13-d]; and Ea is Formula (c1) or Formula (c4) shown as specificexamples of Formula (C) described in Aspect [1-15]).

More specifically, preferable aspects of n, p, h, q, q1, r1, s, the ringA′, V, T, J_(1a), J₂, R¹, R^(2a), R^(2b), R⁸, R⁹, R¹³, R¹⁴, and Ea arethe same as the preferable aspects described in any one of Aspects [1-1]to [1-15] and subordinate Aspects thereof.

In Formula (III-1)-1, Ea is preferably Formula (c1).

In Formula (III-1)-1, any one of q and s is preferably 1 or more.

In Formula (III-1)-1, more preferably, Ea is Formula (c1) and any one ofq and s is 1 or more.

The cyclic amide structure bonded to the ring B of Formula (III-1)-1 isPartial Structural Formula (B-Het)-1 described in Aspect [1-14-e], andpreferable examples of the cyclic amide structure include Formula(B-Het)-1a, (B-Het)-1b, Formula (B-Het)-1c, Formula (B-Het)-1d, Formula(B-Het)-1e, and Formula (B-Het)-1f described in Aspect [1-14-e-1]. InFormula (III-1)-1, a compound having Formula (B-Het)-1a is Formula(III-1)-1-1a, a compound having Formula (B-Het)-1b is Formula(III-1)-1-1b, a compound having Formula (B-Het)-1c is Formula(III-1)-1-1c, a compound having Formula (B-Het)-1d is Formula(III-1)-1-1d, a compound having Formula (B-Het)-1e is Formula(III-1)-1-1e, and a compound having Formula (B-Het)-1f is Formula(III-1)-1-1f.

[1-16-2-3] The compound of Formula (III-1)-1 according to Aspect[1-16-2-2] is preferably Formula (III-1-A)-1:

(where n, p, h, J₂, R¹, R^(2a), and R^(2b) are the same as defined inFormula (I); J_(1a) is the same as defined in Formula (B)-1 described inAspect [1-14-a-1]; q, s, the ring A″, V, R⁸, and R⁹ are the same asdefined in Formula (A) or Formula (A)-1 described in Aspect [1-13-c];and q1, r1, R¹³, and R¹⁴ are the same as defined in Formula (AA)described in Aspect [1-13-d]).

More specifically, preferable aspects of n, p, h, q, q1, r1, s, the ringA″, V, J_(1a), J₂, R¹, R^(2a), R^(2b), R⁸, R⁹, R¹³, and R¹⁴ are the sameas the preferable aspects described in any one of Aspects [1-1] to[1-15] and subordinate Aspects thereof.

In Formula (II-1-A)-1, any one of q and s is preferably 1 or more.

The cyclic amide structure bonded to the ring B of Formula (III-1-A)-1is Partial Structural Formula (B-Het)-1 described in Aspect [1-14-e],and preferable examples of the cyclic amide structure include Formula(B-Het)-1a, (B-Het)-1b, Formula (B-Het)-1c, Formula (B-Het)-1d, Formula(B-Het)-1e, and Formula (B-Het)-1 f described in Aspect [1-14-e-1]. InFormula (II-1-A)-1, a compound having Formula (B-Het)-1a is Formula(II-1-A)-1-1a, a compound having Formula (B-Het)-1b is Formula(II-1-A)-1-1b, a compound having Formula (B-Het)-1c is Formula(III-1-A)-1-1c, a compound having Formula (B-Het)-1d is Formula(III-1-A)-1-1d, a compound having Formula (B-Het)-1e is Formula(III-1-A)-1-1e, and a compound having Formula (B-Het)-1f is Formula(III-1-A)-1-1f.

[1-16-2-4] The compound of Formula (III-1)-1 according to Aspect[1-16-2-2] is preferably Formula (III-1-B)-1:

(where n, p, h, J₂, R¹, R^(2a), and R^(2b) are the same as defined inFormula (I); J_(1a) is the same as defined in Formula (B)-1 described inAspect [1-14-a-1]; q, s, the ring A″, V, R⁸, and R⁹ are the same asdefined in Formula (A) or Formula (A)-1 described in Aspect [1-13-c];and q1, r1, R¹³, and R¹⁴ are the same as defined in Formula (AA)described in Aspect [1-13-d]).

More specifically, preferable aspects of n, p, h, q, q1, r1, s, the ringA″, V, J_(1a), J₂, R¹, R^(2a), R^(2b), R⁸, R⁹, R¹³, and R¹⁴ are the sameas the preferable aspects described in any one of Aspects [1-1] to[1-15] and subordinate Aspects thereof.

In Formula (III-1-B)-1, any one of q and s is preferably 1 or more.

The cyclic amide structure bonded to the ring B of Formula (III-1-B)-1is Partial Structural Formula (B-Het)-1 described in Aspect [1-14-e],and preferable examples of the cyclic amide structure include Formula(B-Het)-1a, (B-Het)-1b, Formula (B-Het)-1c, Formula (B-Het)-1d, Formula(B-Het)-1e, and Formula (B-Het)-1f described in Aspect [1-14-e-1]. InFormula (III-1-B)-1, a compound having Formula (B-Het)-1a is Formula(III-1-B)-1-1a, a compound having Formula (B-Het)-1b is Formula(III-1-B)-1-1b, a compound having Formula (B-Het)-1c is Formula(III-1-B)-1-1c, a compound having Formula (B-Het)-1d is Formula(III-1-B)-1-1d, a compound having Formula (B-Het)-1e is Formula(III-1-B)-1-1e, and a compound having Formula (B-Het)-1f is Formula(III-1-A)-1-1f.

[1-16-3] As the compound of Formula (I) according to Aspect [1], apreferable compound is a compound in which the ring A is Formula (A1)-IVand Formula (C) is Formula (c2), that is, Formula (IV-1):

(where n, p, h, J₂, R¹, R^(2a), and R^(2b) are the same as defined inFormula (I) described in Aspect [1]; J_(1a) is the same as defined inFormula (B)-1 described in Aspect [1-14-a-1]; q, r, s, the ring A′, R⁸,R⁹, and R¹⁰ are the same as defined in Formula (A) described in Aspect[1-13-c]; and g1 is the same as defined in Formula (A1)-IV described inAspect [1-13-e-2]).

More specifically, preferable aspects of n, p, h, q, r, s, the ring A′,J_(1a), J₂, R¹, R^(2a), R^(2b) R⁸, R⁹, R¹⁰, and g1 are the same as thepreferable aspects described in any one of Aspects [1-1] to [1-15] andsubordinate Aspects thereof.

[1-16-3-1] As the compound of Formula (I) according to Aspect [1], apreferable compound is a compound in which the ring A is Formula (A3)-IVand Formula (C) is Formula (c2), that is, Formula (IV-3):

(where n, p, h, J₂, R¹, R^(2a), and R^(2b) are the same as defined inFormula (I) described in Aspect [1]; J_(1a) is the same as defined inFormula (B)-1 described in Aspect [1-14-a-1]; q and R⁹ are the same asdefined in Formula (A) described in Aspect [1-13-c]; and R^(10f) is thesame as defined in Formula (A2)-IV described in Aspect [1-13-e-3]).

More specifically, preferable aspects of n, p, h, q, J_(1a), J₂, R¹,R^(2a), R^(2b), R⁹, and R^(10f) are the same as the preferable aspectsdescribed in any one of Aspects [1-1] to [1-15] and subordinate Aspectsthereof.

[1-16-3-2] As the compound of Formula (I) according to Aspect [1], apreferable compound is a compound in which the ring A is Formula (A4)-IVand Formula (C) is Formula (c2), that is, Formula (IV-4):

(where n, p, h, J₂, R¹, R^(2a), and R^(2b) are the same as defined inFormula (I) described in Aspect [1]; J_(1a) is the same as defined inFormula (B)-1 described in Aspect [1-14-a-1]; and Z₁, Z₂, Z₃, and X₂ arethe same as defined in Formula (A4)-IV described in Aspect [1-13-e-8]).

More specifically, preferable aspects of n, p, h, J_(1a), J₂, R¹,R^(2a), R^(2b), Z₁, Z₂, Z₃, and X₂ are the same as the preferableaspects described in any one of Aspects [1-1] to [1-15] and subordinateAspects thereof.

[1-16-4] As the compound of Formula (I) according to Aspect [1], apreferable compound is a compound in which the ring A is Formula (A)-Vand Formula (C) is Formula (c2), that is, Formula (V):

(where n, p, h, J₂, R¹, R^(2a), and R^(2b) are the same as defined inFormula (I) described in Aspect [1]; J_(1a) is the same as defined inFormula (B)-1 described in Aspect [1-14-a-1]; q and s are the same asdefined in Formula (A) described in Aspect [1-13-c]); r is the same asdefined in Formula (AA) described in Aspect [1-13-d]; and R⁸, R⁹, R¹⁰,n1, n2, n3, X₃, and the broken lines are the same as defined in Formula(A)-V described in Aspect [1-13-f]).

More specifically, preferable aspects of n, p, h, q, r, s, J_(1a), J₂,R¹, R^(2a), R^(2b), R⁸, R⁹, R¹⁰, n1, n2, n3, and X₃ are the same as thepreferable aspects described in any one of Aspects [1-1] to [1-15] andsubordinate Aspects thereof.

[1-16-4-1] The compound of Formula (V) according to Aspect [1-16-4] isfurther preferably Formula (V)-1:

(where n, p, h, J₂, R¹, R^(2a), and R^(2b) are the same as defined inFormula (I) described in Aspect [1]; J_(1a) is the same as defined inFormula (B)-1 described in Aspect [1-14-a-1]; and n1 and n2 are the sameas defined in Formula (A)-V described in Aspect [1-13-f]).

More specifically, preferable aspects of n, p, h, J_(1a), J₂, n1, n2,R¹, R^(2a), and R^(2b) are the same as the preferable aspects describedin any one of Aspects [1-1] to [1-15] and subordinate Aspects thereof.

[1-16-4-2] As the compound of Formula (I) according to Aspect [1], apreferable compound is a compound in which the ring A is Formula (AA1)-Vand Formula (C) is Formula (c2), that is, Formula (V-A):

(where n, p, h, J₂, R¹, R^(2a), and R^(2b) are the same as defined inFormula (I) described in Aspect [1]; J_(1a) is the same as defined inFormula (B)-1 described in Aspect [1-14-a-1]; q, s, the ring A′, V, R⁸,and R⁹ are the same as defined in Formula (A) described in Aspect[1-13-c]); r is the same as defined in Formula (AA) described in Aspect[1-13-d]; R¹⁰ and the broken lines are the same as defined in Formula(A)-V described in Aspect [1-13-f]; and n4 is the same as defined inFormula (AA)-V described in Aspect [1-13-f-8]).

More specifically, preferable aspects of n, p, h, q, r, s, the ring A′,V, J_(1a), J₂, R¹, R^(2a), R^(2b), R⁸, R⁹, R¹⁰, and n4 are the same asthe preferable aspects described in any one of Aspects [1-1] to [1-15]and subordinate Aspects thereof.

[1-16-5] As the compound of Formula (I) according to Aspect [1], apreferable compound is a compound in which the ring A is Formula (A)-VI,that is, Formula (VI):

(where X, n, p, h, J₂, R¹, R^(2a), R^(2b), and the broken lines are thesame as defined in Formula (I) described in Aspect [1]; J_(1a) is thesame as defined in Formula (B)-1 described in Aspect [1-14-a-1]; and Rx,Rxa, Rxb, and X₁ (including Ry and Rz) are the same as defined inFormula (A)-VI described in Aspect [1-13-g]). Preferable aspects of X,n, p, h, J_(1a), J₂, R¹, R^(2a), R^(2b), Rx, Rxa, Rxb, and X₁ are thesame as the preferable aspects described in any one of Aspects [1-1] to[1-15] and subordinate Aspects thereof.

Here, as preferable aspects and specific examples of the PartialStructural Formula (A)-VI moiety having a substitutedspiropiperidinylmethyl group described in Aspect [1-13-g], the same asthe preferable aspects and specific examples described in Aspects[1-13-g] and [1-13-g-1] can be mentioned.

[1-16-5-1] As the compound of Formula (I) according to Aspect [1], apreferable compound is a compound in which the ring A is Formula(AA)-VI, that is, Formula (VI-A):

(where X, n, p, h, J₂, R¹, R^(ea), and R^(2b) are the same as defined inFormula (I) described in Aspect [1]; J_(1a) is the same as defined inFormula (B)-1 described in Aspect [1-14-a-1]; q, s, R⁸, and R⁹ are thesame as defined in Formula (A) described in Aspect [1-13-c]; Rxb is thesame as defined in Formula (A)-VI described in Aspect [1-13-g]; and thebroken lines are the binding position of an isothiazolyl group or apiperidinylmethyl group).

More specifically, preferable aspects of X, n, p, h, q, s, J_(1a), J₂,R¹, R^(2a), R^(2b), R⁸, R⁹, and Rxb are the same as the preferableaspects described in any one of Aspects [1-1] to [1-15] and subordinateAspects thereof.

[1-17] As the compound of Formula (I) according to Aspect [1], apreferable compound is Formula (I)-B1 or Formula (I)-B2:

(where n, p, h, j, k, the ring A, X, J₁, J₂, R¹, R^(2a), R^(2b), R³, R⁴,R⁵, and R⁶ are the same as defined in Formula (I) described in Aspect[1]; and W₁, W₂, and W₃ are the same as in Formula (BB1) or Formula(BB2) described in Aspect [1-10]). R^(2a), R^(2b),

More specifically, preferable aspects of n, p, h, j, k, the ring A, X,J₁, J₂, R¹, R^(2a), R^(2b), R³, R⁴, R⁵, and R⁶ are the same as thepreferable aspects described in any one of Aspects [1-1] to [1-15] andsubordinate Aspects thereof. Preferable aspects of G, W₁, W₂, and W₃ arethe same as the preferable aspects described in Aspect [1-10] andsubordinate Aspects thereof.

[1-17-a] As the compound of Formula (I)-B1 or Formula (I)-B2, apreferable compound is a compound in which the ring A is a C₆₋₁₄ arylgroup which is optionally substituted with 1 to 5 L(s) or a 3- to14-membered heterocyclic group which is optionally substituted with 1 to5 L(s) and the linker moiety containing X is Formula (c1) or Formula(c4) described in Aspect [1-15].

A more preferable compound thereof is a compound in which the ring A isa phenyl group which is optionally substituted with 1 to 5 L(s), aphthalazinyl group which is optionally substituted with 1 to 5 L(s), orFormula (A)-VIII described in Aspect [1-13-j] and the linker moietycontaining X is Formula (c1).

A further preferable compound thereof is a compound in which the ring Ais a phenyl group (the phenyl group is optionally substituted with 1 to3 halogen atom(s), 1 to 3 cyano group(s), 1 to 3 C₁₋₆ alkyl group(s), 1to 3 halogenated C₁₋₆ alkyl group(s), 1 to 3 C₁₋₆ alkoxy group(s), or 1to 3 —SF₅), a phthalazinyl group (the phthalazinyl group is optionallysubstituted with 1 to 3 halogen atom(s), 1 to 3 cyano group(s), 1 to 3C₁₋₆ alkyl group(s), 1 to 3 halogenated C₁₋₆ alkyl group(s), 1 to 3 C₁₋₆alkoxy group(s), or 1 to 3 —SF₅), or Formula (A)-VIII and the linkermoiety containing X is Formula (c1).

[1-18] As described above, Aspects [1-1] to [1-17] and subordinateAspects thereof of the present invention, respective preferable aspectsdescribed above, and the definitions of the substituents can beoptionally combined, so that the preferable aspects of the compound ofFormula (I) according to Aspect [1] can be optionally provided.

[1-19] Examples of preferable compounds as the compound of Formula (I)according to Aspect [1] include the following:

-   5-[4-[[3-[4-(2-ethoxyethoxy)-2,6-dimethylphenyl]phenyl]methoxy]phenyl]-1-oxo-1,    2-thiazolidin-3-one (Example 1);-   5-[4-[[3-[4-(2-ethoxyethoxy)-3-fluoro-2,6-dimethylphenyl]phenyl]methoxy]phenyl]-1-oxo-1,2-thiazolidin-3-one    (Example 2);-   5-[4-[[3-[3-fluoro-4-(3-hydroxy-3-methylbutoxy)-2,6-dimethylphenyl]phenyl]methoxy]phenyl]-1-oxo-1,2-thiazolidin-3-one    (Example 3);-   5-[4-[[3-[4-(3-hydroxy-3-methylbutoxy)-2,6-dimethylphenyl]phenyl]methoxy]phenyl]-1-oxo-1,2-thiazolidin-3-one    (Example 4);-   5-[4-[[3-[2,4-dimethyl-6-(3-methylsulfonylpropoxy)pyridin-3-yl]phenyl]methoxy]phenyl]-1-oxo-1,2-thiazolidin-3-one    (Example 5);-   5-[4-[[3-[6-(3-hydroxy-3-methylbutoxy)-2,4-dimethylpyridin-3    yl]phenyl]methoxy]phenyl]-1-oxo-1,2-thiazolidin-3-one trifluoro    acetic acid salt (Example 6);-   5-[4-[[3-[4-(3-hydroxy-3-methylbutoxy)-2,5-dimethylphenyl]phenyl]methoxy]phenyl]-1-oxo-1,2-thiazolidin-3-one    (Example 7);-   5-[4-[[3-[4-(3-hydroxypropoxy)-2,6-dimethylphenyl]phenyl]methoxy]phenyl]-1-oxo    -1,2-thiazolidin-3-one (Example 8);-   5-[4-[[3-[4-[(2R)-2,3-dihydroxypropoxy]-2,6-dimethylphenyl]phenyl]methoxy]phenyl]-1-oxo-1,2-thiazolidin-3-one    (Example 9);-   5-[4-[[3-[4-[3-hydroxy-2-(hydroxymethyl)propoxy)-2,6-dimethylphenyl]phenyl]    methoxy]phenyl]-1-oxo-1,2-thiazolidin-3-one (Example 10);-   5-[4-[[3-[4-(3-aminopropoxy)-2,6-dimethylphenyl]phenyl]methoxy]phenyl]-1-oxo-1,2-thiazolidin-3-one    trifluoro acetic acid salt (Example 11);-   5-[4-[[3-[4-[(3R)-3-hydroxybutoxy]-2,6-dimethylphenyl]phenyl]methoxy]phenyl]-1-oxo-1,2-thiazolidin-3-one    (Example 12);-   5-[4-[[3-[2,6-dimethyl-4-(3-methylsulfonylpropoxy)phenyl]phenyl]methoxy]phenyl]-1-oxo-1,2-thiazolidin-3-one    (Example 13);-   5-[4-[[3-(2,6-dimethylphenyl)phenyl]methoxy]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one    (Example 14);-   5-[4-[[3-[2,6-dimethyl-4-(3-methylsulfonylpropoxy)phenyl]phenyl]methoxy]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one    (Example 15);-   5-[2-chloro-4-[[3-(2,6-dimethylphenyl)phenyl]methoxy]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one    (Example 16);-   5-[4-[[3-(2,6-dimethylphenyl)phenyl]methoxy]-2-methylphenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one    (Example 17);-   5-[4-[[3-(2,6-dimethylphenyl)phenyl]methoxy]phenyl]-4-methyl-1,1-dioxo-1,2,5-thiadiazolidin-3-one    (Example 18);-   5-[4-[[3-(2,6-dimethyl-4-(3-methylsulfonylpropoxy)phenyl]phenyl]methoxy]phenyl]-1,1-dioxo-1,2-thiazolidin-3-one    (Example 19);-   5-[4-[[346-(3-hydroxy-3-methylbutoxy)-2,4-dimethylpyridin-3-yl]phenyl]methoxy]phenyl]-1,1-dioxo-1,2-thiazolidin-3-one    (Example 20);-   5-[4-[[3-(2,6-dimethylphenyl)phenyl]methoxy]phenyl]-1,1-dioxo-1,2,6-thiadiazinane-3-one    (Example 21);-   5-[4-[[3-(2,6-dimethylphenyl)phenyl]methoxy]phenyl]-1,1-dioxo-1,2-thiazinan-3-one    (Example 22);-   5-(4-(((R)-4-(6-(3-hydroxy-3-methylbutoxy)-2-methylpyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)oxy)phenyl)-1-oxo-1,2-thiazolidin-3-one (A)    (Example 23);-   5-[4-[[(1R)-4-[6-(3-hydroxy-3-methylbutoxy)-2,6-dimethylphenyl]-2,3-dihydro-1H-inden-1-yl]oxy]phenyl]-1-oxo-1,2-thiazolidin-3-one (A)    (Example 24);-   4-(((1R)-1-(4-(1-oxo-1,2-thiazolidin-3-one-5-yl)phenoxy)-2,3-dihydro-1H-inden-4-yl)oxy)benzonitrile (A)    (Example 25);-   4-(((1R)-1-(4-(1,1-dioxo-1,2,6-thiadiazinan-3-one-5-yl)phenoxy)-2,3-dihydro-1H-inden-4-yl)oxy)benzonitrile    (Example 26);-   5-(4-(((R)-4-phenoxy-2,3-dihydro-1H-inden-1-yl)oxy)phenyl)-1-oxo-1,2-thiazolidin-3-one    (Example 27);-   5-(4-((7-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)oxy)phenyl)-1-oxo-1,2-thiazolidin-3-one    (Example 28);-   5-(4-(((R)-4-bromo-2,3-dihydro-1H-inden-1-yl)oxy)phenyl)-1-oxo-1,2-thiazolidin-3-one    (Example 29);-   5-(4-(((R)-4-(2,6-dimethyl-4-(3-(methylsulfonyl)propoxy)phenyl)-2,3-dihydro-1H-inden-1-yl)oxy)phenyl)-1-oxo-1,2-thiazolidin-3-one    (Example 30);-   5-[4-[[3-[2,6-dimethyl-4-(3-methylsulfonylpropoxy)phenyl]phenyl]methoxy]phenyl]-1,1-dioxo-1,2-thiazinan-3-one    (Example 31);-   4-(((1R)-1-(4-(1,1-dioxo-3-oxo-1,2-thiazinan-5-yl)phenoxy)-2,3-dihydro-1H-inden-4-yl)oxy)benzonitrile    (Example 32);-   5-(4-(((R)-4-bromo-2,3-dihydro-1H-inden-1-yl)oxy)phenyl)-1,1-dioxo-1,2-thiazinane-3-one    (Example 33);-   5-(4-(((R)-4-(4-(3-hydroxy-3-methylbutoxy)-2,6-dimethylphenyl)-2,3-dihydro-1H-inden-1-yl)oxy)phenyl)-1,1-dioxo-1,2-thiazinan-3-one    (Example 34); and-   5-[4-[[3-[6-(3-hydroxy-3-methylbutoxy)-2,4-dimethylpyridin-3-yl]phenyl]methoxy]phenyl]-1,1-dioxo-1,2-thiazinan-3-one    (Example 35),    a salt of the compound, a solvate of the compound or the salt, and    an optical isomer thereof. Examples of the above preferable    compounds also include the compounds of Structural Formulae 3 to 12    below in (Example 1P) to (Example 157P), a salt of the compound, a    solvate of the compound or the salt, and an optical isomer thereof.

[1-19-1] In the compound of Formula (I) according to Aspect [1] or ofFormula (I)-1 according to Aspect [1-16], compounds produced byoptionally combining the groups of Partial Structural Formula (A)-(C)(on the left of the wavy line) and Partial Structural Formula (B)-1 (onthe right of the wavy line) in Formula (I)-1 can be produced optionally:

More specifically, Partial Structural Formula (B)-1 is a groupoptionally selected from Formula (B1a-het1) to Formula (B1a-het5) orFormula (B2a-het1) to Formula (B2a-het5) described below, and PartialStructural Formula (A)-(C) is a group optionally selected from Formula(a-1) to Formula (a-109) described below.

The compounds produced by combining these partial structural formulaeare exemplified as specific compounds of the compound of Formula (I) orFormula (I)-1. For example, a compound of Formula (a1-B1a-het1):

produced by combining Formula (B1a-het1) with Formula (a-1) isexemplified as the specific compound. In such a specific compound, acompound in which the moiety corresponding to X is exchanged from anoxygen atom to —NH— or from —NH— to an oxygen atom can also beoptionally produced, and the thus produced compound is also exemplifiedas the specific compound.

[1-19-2] In the compound of Formula (I) according to Aspect [1] or ofFormula (I)-B1 or Formula (I)-B2 according to Aspect [1-17], compoundsproduced by optionally combining the groups of Partial StructuralFormula (A)-(C) (on the left of the left wavy line), Partial StructuralFormula (BB1) or Formula (BB2) (between the two wavy lines), PartialStructural Formula (B-Het) (on the right of the right wavy line) inFormula (I)-B1 or Formula (I)-B2 can also be produced optionally:

More specifically, Partial Structural Formula (B-Het) is a groupoptionally selected from Formula (het1) to Formula (het9). PartialStructural Formula (BB1) or Formula (BB2) is a group optionally selectedfrom Formula (b-1) to Formula (b-5), and Partial Structural Formula(A)-(C) is a group optionally selected from Formula (a-37) to Formula(a-40) exemplified in Aspect [1-19-1] or Formula (a-94) to Formula(a-99) below.

The compounds produced by combining these partial structural formulaeare exemplified as specific compounds of the compound of Formula (I),Formula (I)-B1, or Formula (I)-B2. For example, a compound of Formula(a94-b1-het6):

produced by combining Formula (het6), Formula (b-1), and Formula (a-94)is exemplified as the specific compound.

[2] A second aspect of the present invention is a pharmaceuticalcomposition, characterized by containing, as an active ingredient, atleast one of the compound of Formula (I), a pharmaceutically acceptablesalt of the compound, and a pharmaceutically acceptable solvate of thecompound or the salt.

[3] A third aspect of the present invention is a prophylactic agentand/or a therapeutic agent for a GPR40-involving disease, characterizedby containing, as an active ingredient, at least one of the compound ofFormula (I), a pharmaceutically acceptable salt of the compound, and apharmaceutically acceptable solvate of the compound or the salt.

[3-1] Specifically, a prophylactic agent and/or a therapeutic agent foreach disease of diabetes [more specifically, any one of or all of Type 1diabetes (insulin-dependent diabetes), Type 2 diabetes(non-insulin-dependent diabetes), and boederline type diabetes (impairedglucose tolerance (IGT) and/or impaired fasting glycemia (IFG))],obesity, and adiposity, characterized by containing, as an activeingredient, at least one of the compound of Formula (I), apharmaceutically acceptable salt of the compound, and a pharmaceuticallyacceptable solvate of the compound or the salt. An inhibitor of Type 2diabetes in the impaired glucose tolerance is also included in examplesof the above prophylactic agent and therapeutic agent. A therapeuticagent for sulfonylurea secondary failure diabetes is also included inthe examples thereof, and by the therapeutic agent, also in(administration-ineffective) diabetic patients who cannot obtain asatisfactory hypoglycemic effect even by being administrated with asulfonylurea agent (such as glibenclamide and glimepiride) or arapid-acting insulin secretagogues (such as mitiglinide), insulinsecretion effect or hypoglycemic effect can be obtained.

Here, in relationship between the blood glucose level and the disease,the diabetes is characterized by exhibiting a fasting blood glucoselevel of 126 mg/dL or more, or a casual blood glucose level or a 2 hoursvalue of the 75 g oral glucose tolerance test (OGTT) of 200 mg/dL ormore. The boederline type diabetes (also called glucose tolerancedisorders) refers to an impaired fasting glycemia (IFG) in which thefasting blood glucose level is 110 mg/dL or more and less than 126 mg/dLand/or an impaired glucose tolerance (IGT) in which a 2 hours value ofthe 75 g OGTT is 140 mg/dL or more and less than 200 mg/dL.

The insulin resistance refers to a pathological condition in whichinsulin becomes unable to lower the blood glucose level in the organismand is evaluated by a quantitative glucose clamp technique or HOMA-IR inclinical practice. It is known that the insulin resistance causes ahyperinsulinemia and becomes a risk of a hypertension and a coronaryartery disease.

The “adiposity” is defined by the Japan Society for the Study of Obesityas “a pathological condition requiring medically a weight reduction inthe case where an obesity-derived or -related health impairment iscombined or such a combination is expected”. The “obesity” defined hereis evaluated by measuring BMI (body mass index, kg/m²). Generally, abody having a BMI of 25 or more is diagnosed as obesity. Examples of theresult of the therapy include the reduction of BMI.

[4] A fourth aspect of the present invention is an insulinsecretagogues, characterized by containing, as an active ingredient, atleast one of the compound of Formula (I), a pharmaceutically acceptablesalt of the compound, and a pharmaceutically acceptable solvate of thecompound or the salt.

[5] A fifth aspect of the present invention is a GPR40 activating agentcontaining one or more of the compound of Formula (I), apharmaceutically acceptable salt of the compound, and a pharmaceuticallyacceptable solvate of the compound or the salt.

In the second to fifth aspects and preferable aspects thereof, morepreferable substituents and a combination thereof in Formula (I) areaccording to descriptions described in the first aspect.

In each aspect as described in [1] to [5] of the present invention, itis preferable to use a compound having a EC₅₀ value of preferably, 3 μMor less, more preferably, 1 μM or less, further preferably, 300 nM orless, and most preferably, 100 nM or less, when the GPR40 agonist actionis measured by a method accordingly selected (for example, the belowdescribed pharmacological test example 1 (an agonist action on GPR40 ofhuman origin)).

In the above aspects of the present invention, the “therapeutic agent”is not only for treating diseases or symptoms, but also for improvingdiseases or symptoms.

In all of the above aspects, when the term “compound” is used, thecompound refers also to a “pharmaceutically acceptable salt of thecompound”. In addition, there is the case where the compound of thepresent invention has an asymmetric carbon, and thus, the compound ofthe present invention includes a mixture of various stereoisomers suchas a geometric isomer, a tautomer, and an optical isomer, and anisolated stereoisomer. The compound of Formula (I) may have an axialasymmetry due to a steric hindrance and an isomer caused by the axialasymmetry (axial chirality) is also included in the compound of theFormula (I). The isolation and the purification of such stereoisomerscan be performed by a person skilled in the art by an ordinary techniquethrough an optical resolution or an asymmetric synthesis using apreferential crystallization or a column chromatography.

The compound of Formula (I) of the present invention may form an acidaddition salt or a salt with a base depending on the type of thesubstituent. Such salt is not particularly limited so long as the saltis a pharmaceutically acceptable salt. Specific examples thereof includeacid addition salts with: mineral acids such as hydrochloric acid,hydrobromic acid, hydriodic acid, sulfuric acid, nitric acid, andphosphoric acid; organic carboxylic acids, for example, an aliphaticmonocarboxylic acid such as formic acid, acetic acid, propionic acid,butyric acid, valeric acid, enanthic acid, capric acid, myristic acid,palmitic acid, stearic acid, lactic acid, sorbic acid, and mandelicacid, an aromatic monocarboxylic acid such as benzoic acid and salicylicacid, an aliphatic dicarboxylic acid such as oxalic acid, malonic acid,succinic acid, fumaric acid, maleic acid, malic acid, and tartaric acid,an aliphatic tricarboxylic acid such as citric acid, cinnamic acid,glycolic acid, pyruvic acid, oxylic acid, salicylic acid, andN-acetylcysteine; organic sulfonic acids, for example, an aliphaticsulfonic acid such as methanesulfonic acid, ethanesulfonic acid, and2-hydroxyethanesulfonic acid, and an aromatic sulfonic acid such asbenzenesulfonic acid and p-toluenesulfonic acid; and acidic amino acidssuch as aspartic acid and glutamic acid, salts (including, besides monosalts, disodium salts and dipotassium salts) with a metal, for example,alkali metals such as lithium, sodium, potassium, and cesium, andalkaline earth metals such as magnesium, calcium, and barium, salts witha metal such as aluminum, iron, copper, nickel, cobalt, and zinc, saltswith an organic base such as methylamine, ethylamine, tert-butylamine,tert-octylamine, diethylamine, triethylamine, cyclohexylamine,dibenzylamine, ethanolamine, diethanolamine, triethanolamine,piperidine, morpholine, pyridine, lysine, arginine, ornithine,ethylenediamine, N-methylglucamine, glucosamine, a phenylglycine alkylester, and guanidine, and salts with glycine, histidine, choline, andammonium.

These salts can be obtained by an ordinary method including, forexample, mixing an equivalent of the compound of the present inventionwith a solution containing a desired acid, base, or the like, andcollecting a desired salt by filtration or distillation-off of asolvent. The compound of the present invention or a salt of the compoundcan form a solvate with a solvent such as water, ethanol, and glycerol.

The salt of the compound of the present invention includes a mono-saltand a di-salt. The compound of the present invention can form both of anacid addition salt and a salt with a base simultaneously depending onthe type of the substituent in the side chains. Further, the presentinvention encompasses also hydrates, various pharmaceutically acceptablesolvates, and crystal polymorphs of the compound of Formula (I) of thepresent invention. Here, needless to say, the present invention is notlimited to the compounds described in Examples below and encompasses allof the compounds of Formula (I) of the present invention andpharmaceutically acceptable salts of the compounds.

The compound of the present invention may be labeled with an isotope(such as ³H, ¹⁴C, and ³⁵S).

[Method for producing the compound of the present invention]

Methods for producing the compound of Formula (I) of the presentinvention will be described below.

The compound of Formula (I) of the present invention, a salt of thecompound, and a solvate of the compound or the salt can be produced by acombination of commonly known chemical production methods. Typicalproduction methods will be described below.

In each Formula in the production methods below, each definition of ringA, ring B, ring A′, ring A″, ring A′″, ring B′, X, V, T, J₁, J_(1a), J₂,R¹, R^(2a), R^(2b), R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R^(11a), R^(11b),R^(11c), R^(12a), R^(12b), R^(12c), R¹³, R^(13a), R¹⁴, n, p, q, q1, q2,r, r1, s, h, j, k, f, g, g1, X₃, n1, n2, n3, n4, Z₁, Z₂, Z₃, Rx, Rxa,Rxb, X₁, and the like is the same as each definition in Formula (I),Formula (A), Formula (A)-1, Formula (AA), Formula (A1)-IV, Formula(A2)-IV, Formula (A)-V, Formula (AA)-V, Formula (A)-VI, and Formula(B)-I described in the first aspect above unless otherwise specified.

In the production methods, the definition of m is an integer of 1 or 2.

In the production methods, the definition of h2 is an integer of 0 to 2.

In the production methods, the definition of g-1 is an integer of 0 to3.

In the production methods, the definition of R′ is a C₁₋₆ alkyl groupsuch as a methyl group, an ethyl group, and a t-butyl group unlessotherwise specified.

In the production methods, the definition of R″ is a hydrogen atom, ahydroxy group, or a C₁₋₆ alkoxy group such as a methoxy group and anethoxy group unless otherwise specified.

In the production methods, each definition of Y, Y₁, and Y₂ is a halogenatom, a nitro group, a protected imino group (—NP¹ ₂), a formyl group,or an ester group unless otherwise specified.

In the production methods, the definition of Z is a leaving groupincluding a hydroxy group, a halogen atom, and a sulfonyloxy group suchas a methanesulfonyloxy group, a p-toluenesulfonyloxy group, and atrifluoromethanesulfonyloxy group unless otherwise specified.

In the production methods, the definition of W is boronic acid, aboronic ester, or a trifluoroborate salt unless otherwise specified.

In the production methods, for the definitions of W¹ and W², W² isboronic acid, a boronic ester, or a trifluoroborate salt when W¹ is ahydroxy group, a halogen atom, or a trifluoromethanesulfonyloxy group,and W² is a hydroxy group, a halogen atom, or atrifluoromethanesulfonyloxy group when W¹ is boronic acid, a boronicester, or a trifluoroborate salt unless otherwise specified.

In the production methods, the definition of * is a chiral center.

In the production methods, each definition of P¹, P², P³, P⁴, and P⁵ isa protective group for a hydroxy group (—OH), a thiol group (—SH), or animino group (—NH—) unless otherwise specified. Examples of theprotective group for a hydroxy group include an alkyl group such as amethyl group; an alkoxyalkyl group such as a methoxymethyl group, amethoxyethoxymethyl group, and a tetrahydropyranyl group; an arylmethylgroup such as a benzyl group and a triphenylmethyl group; a silyl groupsuch as a trimethylsilyl group, a triethylsilyl group, and at-butyldimethylsilyl group; an alkanoyl group such as an acetyl groupand a pivaloyl group; an aroyl group such as a benzoyl group; analkoxycarbonyl group such as a t-butoxycarbonyl group; and anarylmethoxycarbonyl group such as a benzyloxycarbonyl group. Examples ofthe protective group for a thiol group include an alkyl group such as amethyl group; an arylmethyl group such as a benzyl group and atriphenylmethyl group; an alkanoyl group such as an acetyl group and apivaloyl group; and an aroyl group such as a benzoyl group. Examples ofthe protective group for an imino group include an alkanoyl group suchas an acetyl group; an alkoxycarbonyl group such as a methoxycarbonylgroup, an ethoxycarbonyl group, and a t-butoxycarbonyl group; anarylmethoxycarbonyl group such as a benzyloxycarbonyl group, apara-methoxybenzyloxycarbonyl group, and a para-nitrobenzyloxycarbonylgroup; an arylmethyl group such as a benzyl group, a para-methoxybenzylgroup, a dimethoxybenzyl group, and a triphenylmethyl group; and anaroyl group such as a benzoyl group.

Deprotection methods of such protective groups are different dependingon the chemical properties of a protected reactive group (a hydroxygroup, a thiol group, or an imino group) and an employed protectivegroup. For example, an acyl-type protective group such as an alkanoylgroup, an alkoxycarbonyl group, and an aroyl group can be hydrolyzedusing a suitable base such as an alkali metal hydroxide includinglithium hydroxide, sodium hydroxide, and potassium hydroxide for thedeprotection. An alkoxyalkyl-type protective group such as amethoxymethyl group, a methoxyethoxymethyl group, and atetrahydropyranyl group, a substituted methoxycarbonyl-type protectivegroup such as a t-butoxycarbonyl group and apara-methoxybenzyloxycarbonyl group, and a silyl-type protective groupsuch as a triethylsilyl group and a t-butyldimethylsilyl group can beremoved using a suitable acid such as acetic acid, hydrochloric acid,hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid,and trifluoromethanesulfonic acid or a combination of them. Thesilyl-type protective group can also be removed using a suitablefluorine ion (F⁻) generating reagent such as tetrabutylammonium fluorideand hydrogen fluoride. An arylmethoxycarbonyl group such as abenzyloxycarbonyl group, a para-methoxybenzyloxycarbonyl group, and apara-nitrobenzyloxycarbonyl group and an arylmethyl group such as abenzyl group can be removed by hydrogenolysis using a palladium carboncatalyst. A benzyl group can be removed by Birch reduction usingmetallic sodium in liquid ammonia. A triphenylmethyl group can beremoved using a suitable acid such as acetic acid, hydrochloric acid,hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid,and trifluoromethanesulfonic acid or a combination of them. It can alsobe removed by Birch reduction using metallic sodium in liquid ammoniaand removed by hydrogenolysis using a palladium carbon catalyst.

During the production of the compound of Formula (I) of the presentinvention, when it has a reactive group such as a hydroxy group, anamino group, and a carboxy group, such a group may be properly protectedin any reaction step, and the protective group may be removed in asuitable step.

Methods for introducing and removing such protective groups are properlyperformed depending on the type of a group to be protected or aprotective group. For example, such introduction and removal can beperformed by methods described in [Protective Groups in OrganicSynthesis, edited by Greene et al., the fourth edition (2007), JohnWiley & Sons].

Required starting materials are commercially available or can be easilyobtained from commercial products by usual production methods in organicchemistry.

Reaction conditions in the production methods are as follows unlessotherwise specified. The reaction temperature is in a range from −78° C.to the reflux temperature of a solvent, and the reaction time is a timesufficient for a reaction. Examples of the reaction inert solventinclude, but are not limited to, an aromatic hydrocarbon solvent such astoluene, benzene, and xylene; an alcoholic solvent such as methanol,ethanol, and 2-propanol; a polar solvent such as water, acetonitrile,N,N-dimethylformamide, dimethyl sulfoxide, and1,3-dimethyl-2-imidazolidinone; a basic solvent such as triethylamineand pyridine; a halogenated solvent such as chloroform, methylenechloride, and 1,2-dichloroethane; an ether solvent such as1,2-dimethoxyethane, cyclopentyl methyl ether, diethyl ether,tetrahydrofuran, and dioxane; and a mixed solvent of them. Such solventsare properly selected depending on reaction conditions. Examples of thebase include, but are not limited to, an inorganic base such as sodiumcarbonate, potassium carbonate, cesium carbonate, sodium hydroxide,potassium hydroxide, and sodium hydride; and an organic base such astriethylamine, N,N-diisopropylethylamine, pyridine, N,N-dialkylaniline,lithium diisopropylamide, and lithium bistrimethylsilylamide. Examplesof the acid include, but are not limited to, a mineral acid such ashydrochloric acid, sulfuric acid, and nitric acid; and an organic acidsuch as methanesulfonic acid and p-toluenesulfonic acid.

Hereinafter, production methods will be described, but the presentinvention is not limited to these methods.

The compound of Formula (I) of the present invention can be obtained bya production method suitable for the type of the ring including asaturated amide structure having —S(O)n-NH—CO—. A material compound forthe compound is typically shown as Formula (IX).

In the formulae in the production method, <Het> generally means aconversion part into the ring structure of a saturated cyclic amidestructure that is bonded to the ring B and has —S(O)n-NH—CO— (n is aninteger of 0 to 2), examples of which include W (for example, boronicacid, a boronic ester, and a trifluoroborate salt) and Y (for example, ahalogen atom, a nitro group, a protected imino group (—NP¹ ₂), a formylgroup, and an ester group) in the production method, and a molecularchain to form the saturated cyclic amide structure.

(1) Methods for producing the compound of Formula (I)-1a or Formula(I)-2a of the present invention will be described below.

<Production Method A>

<When R^(2a)=R^(2b)=H and R^(11a)=H in Formula (I)-1a above>

<Step 1>

The compound of Formula (IX)-1a obtained in (Production Method E) or(Production Method F) described later is subjected to isothiazole ringformation reaction. In accordance with methods known in literatures, forexample, the methods described in [Heterocyclic Compounds, New Edition,Applications, pp. 41-57 (2004), Kodansha Ltd.], [Chemische Berichte,vol. 94, p. 2950 (1961)], and [Chemische Berichte, vol. 96, p. 944(1963)], a compound of (I)-1a-1 can be produced by reacting the compoundof Formula (IX)-1a with a thiol (SH) source such as sodium hydrosulfideand hydrogen sulfide gas in a reaction inert solvent such as methanol,ethanol, and water or a mixed solvent of them at a temperature from 0°C. to a reflux temperature of the solvent, and then by reacting theobtained thiol adduct in the presence of a halogen such as iodine andbromine and in the presence or absence of a base such as pyridine andpotassium carbonate in a reaction inert solvent such as methanol,ethanol, ethyl acetate, and water or a mixed solvent of them at atemperature from 0° C. to a reflux temperature of the solvent.

<Step 2>

The sulfur atom in the compound of Formula (I)-1a-1 is oxidized. Inaccordance with methods known in literatures, for example, the methoddescribed in [Jikken Kagaku Koza (Experimental Chemistry Course), thefourth edition, vol. 20, Organic Synthesis V, Oxidation Reaction, pp.276-280 (1992), Maruzen Co., Ltd.], a compound of Formula (I)-1a-2 canbe produced by reacting the compound of Formula (I)-1a-1 in the presenceof a peracid or a peroxide such as hydrogen peroxide water,m-chloroperbenzoic acid (MCPBA), peracetic acid, trifluoroperaceticacid, Oxone (registered trademark) (DuPont), and tert-butylhydroperoxide(TBHP) in a reaction inert solvent including a halogenated solvent suchas dichloromethane and chloroform, an aromatic hydrocarbon solvent suchas toluene and benzene, and a polar solvent such as acetonitrile,methanol, acetone, and water or in a mixed solvent of them at atemperature from 0° C. to a reflux temperature of the solvent. In theoxidation reaction, selection of an oxidizing agent and suitableselection of equivalent weight of a reagent, a reaction temperature, areaction time, a solvent, and the like can produce a sulfoxide (n=1) anda sulfone (n=2) separately. Such sulfoxide and sulfone can be separatedby common techniques such as column chromatography.

<Step 3>

The compound of Formula (I)-1a-2 is subjected to reduction. Inaccordance with methods known in literatures, for example, the methoddescribed in [Japan Institute of Heterocyclic Chemistry, vol. 64, pp.101-120 (2004)], the compound of Formula (I)-1a can be produced byreacting the compound of Formula (I)-1a-2 in the presence of a reducingagent such as lithium tri(sec-butyl)borohydride (L-selectride),potassium tri(sec-butyl)borohydride, lithium borohydride, and Raneynickel (Raney-Ni)-formic acid or a reducing agent such as a hydride of ametal or a metalloid and a complex compound of them in a reaction inertsolvent including an ether solvent such as tetrahydrofuran, diethylether, and dioxane, an aromatic hydrocarbon solvent such as toluene andbenzene, and a polar solvent such as acetonitrile and methanol or in amixed solvent of them at a temperature from −78° C. to a refluxtemperature of the solvent.

<Step 4>

In accordance with methods known in literatures, for example, the methoddescribed in [Jikken Kagaku Koza (Experimental Chemistry Course), thefourth edition, vol. 26, Organic Synthesis VIII, Asymmetric Synthesis,Reduction, Sugar, and Labelled Compound, pp. 23-68 (1992), Maruzen Co.,Ltd.], the compound of Formula (I)-1a-3 as an optically active compoundof Formula (I)-1a can be produced by reaction in the presence of thecompound of Formula (I)-1a-2 in the presence of, for example, opticallyactivedichloro[bis(diphenylphosphino)binaphthyl][diphenylethylenediamine]rutheniumand a basic reagent such as potassium hydroxide and potassium t-butoxidein a hydrogen gas atmosphere using 2-propanol as a solvent at atemperature from room temperature to a reflux temperature of thesolvent. Alternatively, the compound of Formula (I)-1a-3 as an opticallyactive compound can be produced by reaction in the presence of atransition-metal complex such aschlorotris(triphenylphosphine)rhodium(I), a reagent such as opticallyactive 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl, and a hydrogensource such as hydrogen and formic acid-triethylamine using a solventsuch as ethanol at a temperature from room temperature to a refluxtemperature of the solvent.

In the production methods below, when an isothiazole ring is subjectedto reduction, a corresponding optically active compound can be obtainedby the reduction in accordance with <Step 4> in <Production Method A>.

The compounds of Formula (II)-1a and Formula (III)-1a above are includedin the compound of Formula (I)-1a in (Production Method A) and can beproduced by a similar production method. In Formula (II-B), Formula(II-C), Formula (IV-1), Formula (IV-3), Formula (IV-4), Formula (V),Formula (V-A), Formula (VI), Formula (VI-A), Formula (1)-B 1, andFormula (I)-B2 above, the compound having Formula (B-Het)-1a is alsoincluded in the compound of Formula (I)-1a and can be produced by asimilar production method to (Production Method A). These compounds ofFormula (I)-1a are included in the compound of Formula (I).

Similarly, in the production methods in (Production Method B) or later,the compounds of Formula (II)-1a and Formula (III)-1a above and thecompounds having Formula (B-Het)-1a in Formula (II-B), Formula (II-C),Formula (IV-1), Formula (IV-3), Formula (IV-4), Formula (V), Formula(V-A), Formula (VI), Formula (VI-A), Formula (1)-B1, and Formula (I)-B2above are included in the compound of Formula (I)-1a and can be producedby a similar production method, and these compounds of Formula (I)-1aare included in the compound of Formula (I).

When n=0 in (Production Method A), a compound can be produced withoutthe oxidation step in <Step 2>.

Similarly, in the production methods in (Production Method B) or later,it should be understood that when n is not specified to 0, 1, or 2, anoxide (a sulfoxide or a sulfone derivative) in which n=1 or 2 can beproduced in accordance with the oxidation reaction in <Step 2> in(Production Method A) in the oxidation step shown in each reactionscheme or a compound (a sulfenamide derivative) in which n=0 can beproduced without the oxidation step.

<Production Method B>

<When R^(2a)=R^(2b)=H and R^(11a)=H in Formula (I)-1a Above>

<Step 1>

A compound of Formula (B-I) is subjected to isothiazole ring formationreaction. A compound of Formula (B-II) can be produced by reacting thecompound of Formula (B-I) (it is known in the art or can be easilyproduced from a known compound as described later in (Production MethodE) and is a properly protected compound) in a similar manner to that in<Step 1> in (Production Method A).

<Step 2>

The compound of Formula (B-II) is protected with a protective group P².A compound of Formula (B-III) can be produced by reacting the compoundof Formula (B-II) with the protective group P² by a method suitable forthe type of the protective group.

<Step 3>

The protective group P¹ in the compound of Formula (B-III) isdeprotected. A compound of Formula (B-IV) can be produced bydeprotecting the protective group P¹ in the compound of Formula (B-III)by a method suitable for the type of the protective group.

<Step 4>

The compound of Formula (B-IV) is subjected to substitution reactionwith a compound of Formula (B-V).

<When Z=Halogen, Methanesulfonyloxy Group, or p-ToluenesulfonyloxyGroup>

In accordance with methods known in literatures, for example, themethods described in [Jikken Kagaku Koza (Experimental ChemistryCourse), the fourth edition, vol. 20, Organic Synthesis II, Alcohol andAmine, pp. 187-200 and 284-292 (1992), Maruzen Co., Ltd.] and [JikkenKagaku Koza (Experimental Chemistry Course), the fourth edition, vol.20, Organic Synthesis VI, Hetero Element- or Main Group MetalElement-Containing Compound, pp. 319-350 (1992), Maruzen Co., Ltd.], acompound of Formula (B-VI) can be produced by substitution reaction ofthe compound of Formula (B-IV) in the presence of the compound ofFormula (B-V) in the presence or absence of a base such astriethylamine, pyridine, sodium hydride, sodium hydroxide, and potassiumcarbonate in a reaction inert solvent including a halogenated solventsuch as dichloromethane and chloroform, an ether solvent such as diethylether and tetrahydrofuran, an aromatic hydrocarbon solvent such astoluene and benzene, and a polar solvent such as N,N-dimethylformamideor in a mixed solvent of them at a temperature from 0° C. to a refluxtemperature of the solvent.

<When Z=Hydroxy Group, X≠—NR⁷—, and k=0>

In accordance with methods known in literatures, for example, the methoddescribed in [Tetrahedron, vol. 67 (10), pp. 3140-3149 (2011)], acompound of Formula (B-VI) can be produced by reacting the compound ofFormula (B-IV) in the presence of the compound of Formula (B-V) in thepresence of a base such as potassium tert-butoxide and a catalyst suchas copper acetate in a reaction inert solvent including an ether solventsuch as diethyl ether, tetrahydrofuran, and 1,4-dioxane and an aromatichydrocarbon solvent such as toluene and benzene or in a mixed solvent ofthem at a temperature from 0° C. to a reflux temperature of the solvent.

<When Z=Hydroxy Group, X=Nitrogen Atom, and k=0>

In accordance with methods known in literatures, for example, themethods described in [WO 2010/143733 pamphlet, p. 71, [0179]: Step 2 inReaction scheme 1], [Tetrahedron Letters, vol. 36, pp. 63733-6374(1995)], and [Tetrahedron Letters, vol. 38, pp. 5831-5834 (1997)], acompound of Formula (B-VI) can be produced by Mitsunobu reaction of thecompound of Formula (B-IV) in the presence of the compound of Formula(B-V) in the presence of an organophosphorus compound such astriphenylphosphine and an azo compound such as an azodicarboxylic acidester and azodicarboxylic amide in a reaction inert solvent including ahalogenated solvent such as dichloromethane and chloroform, an ethersolvent such as diethyl ether and tetrahydrofuran, an aromatichydrocarbon solvent such as toluene and benzene, and a polar solventsuch as N,N-dimethylformamide or in a mixed solvent of them at atemperature from 0° C. to a reflux temperature of the solvent.

The compound of Formula (B-V) used in the step is known in the art orcan be produced from a corresponding known compound in accordance withmethods known in literatures as described later in (Production MethodJ), (Production Method J-1), (Production Method J-2), (Production MethodJ-3), (Production Method J-4), (Production Method J-5), and (ProductionMethod J-6). For example, it can be produced from a correspondingcompound in accordance with the methods described in [WO 2005/063729pamphlet, Reference Examples 2 and 3 and the like], [WO 2005/086661pamphlet, Example 18 and the like], [WO 2008/001931 pamphlet, ReactionScheme 2, Reference Examples 15-19, and the like], [WO 2009/039943pamphlet, pp. 51-52], [WO 2009/054423 pamphlet, Production Examples 12,24, 37, and the like], [WO 2010/085525 pamphlet, Examples 2-5,3-3,4-4,and the like], and [WO 2010/091176 pamphlet, Examples 1-3 and the like].Examples of the compound include compounds that are obtained by properlyprotecting the compounds in Example 25-5 and the like.

The compound that is shown as Formula (I) in WO 2009/039943 pamphlet andthat has a similar formula to Formula (A)-IX in the present applicationis represented by Formula III described in WO 2009/039943 pamphlet, p.52 as Formula (B-V), and the compound is reacted under the condition of<When Z≠hydroxy group> above to produce the compound of Formula (B-VI)(X=nitrogen atom).

<Step 5>

The sulfur atom in the compound of Formula (B-VI) is oxidized. Acompound of Formula (B-VII) can be produced by reacting the compound ofFormula (B-VI) in a similar manner to that in <Step 2> in (ProductionMethod A).

<Step 6>

The protective group P² in the compound of Formula (B-VII) isdeprotected. A compound of Formula (I)-1a-2 can be produced bydeprotecting the protective group P² in the compound of Formula (B-VII)by a method suitable for the type of the protective group.

<Step 7>

The compound of Formula (B-VI) is simultaneously subjected tooxidization of the sulfur atom and deprotection. When the protectivegroup of P² is a protective group capable of being deprotected by acommon oxidation method, a compound of Formula (I)-1a-2 can be producedby reacting the compound of Formula (B-VI) in a similar manner to thatin <Step 2> in (Production Method A).

<Step 8>

The compound of Formula (I)-1a-2 is subjected to reduction. The compoundof Formula (I)-1a can be produced by reacting the compound of Formula(I)-1a-2 in a similar manner to that in <Step 3> in (Production MethodA).

<Production Method C>

<When R^(2b)=H and R^(11b)=H in Formula (I)-1a or Formula (I)-2a Above>

<Step 1>

A compound of Formula (C-I) obtained in (Production Method H),(Production Method H-1), (Production Method H-2), or (Production MethodH-3) described later is subjected to substitution reaction with acompound of Formula (C-II) (Formula (G-III)a or Formula (I-I)) obtainedin (Production Method I) described later. In accordance with methodsknown in literatures, for example, the methods described in [JikkenKagaku Koza (Experimental Chemistry Course), the fifth edition, vol. 18,Synthesis of Organic Compound VI, Organic Synthesis Using Metal, pp.327-352 (2004), Maruzen Co., Ltd.] and [Journal of Medicinal Chemistry,vol. 48 (20), pp. 6326-6339 (2005)], a compound of Formula(I)-1a-2/Formula (I)-2a-2 can be produced by reacting the compounds ofFormula (C-I) and Formula (C-II) in the presence of three reagents of apalladium catalyst, a phosphine reagent or an alkylammonium halidereagent, and a base reagent using a reaction inert solvent such astoluene, xylene, N,N-dimethylformamide, and N,N-dimethylacetamide or amixed solvent of them at a temperature from 0° C. to a refluxtemperature of the solvent. Examples of the palladium catalyst includepalladium(II) acetate, tetrakis triphenylphosphine palladium,tris(dibenzylideneacetone)dipalladium,bis(dibenzylideneacetone)palladium, and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II). Examples ofthe phosphine reagent include triphenylphosphine,tris(tert-butyl)phosphine, tris(o-tolyl)phosphine,2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl,2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, anddicyclohexylphosphino-2′,4′,6′-trisisopropylbiphenyl (Xphos). Examplesof the base reagent include sodium carbonate, cesium carbonate,potassium carbonate, triethylamine, N,N-diisopropylethylamine, andpotassium phosphate. In the reaction above, in place of the phosphinereagent, an alkylammonium halide reagent such as tetramethylammoniumchloride and tetrabutylammonium chloride may be used.

Formula (C-II) used in this step is a compound of Formula (G-III)adescribed later when n=0 and is a compound of Formula (I-I) describedlater when n≠0.

<Step 2>

The compound of Formula (I)-1a-2/Formula (I)-2a-2 is subjected toreduction.

The compound of Formula (I)-1a/Formula (I)-2a can be produced byreacting the compound of Formula (I)-1a-2/Formula (I)-2a-2 in a similarmanner to that in <Step 3> in (Production Method A).

In the present specification, when n=1 in Formula (I)-1a-2/Formula(I)-2a-2 and Formula (I)-1a/Formula (I)-2a above, Formula(I)-1a-2/Formula (I)-2a-2 and Formula (1)-1a/Formula (I)-2a includeoptical isomers. A compound derived from an enantiomer A (I-I-A) thathas a shorter column elution time when optically active Formula (I-I)obtained in (Production Method I) described later is separated by achiral column is represented by Formula (I)-1a-2 (A)/Formula (I)-2a-2(A).

Isomers (diastereomers) of Formula (I)-1a (A)/Formula (I)-2a (A) thatare obtained by reduction of the compound in a similar manner to that in<Step 3> in (Production Method A) can be separated through opticalresolution using chiral column chromatography or asymmetric synthesis bya person skilled in the art based on conventional techniques.

For example, each diastereomer can be obtained using preparativechromatography as in Step 2 in Example 7 described later. In the presentinvention, in the preparative chromatography of a mixture of thediastereoisomers, a diastereomer having a shorter elution time isrepresented as a, while a diastereomer having a longer elution time isrepresented as b, and the diastereomers are correspondingly representedby Formula (I)-1a (A)-a/Formula (I)-2a (A)-a and Formula (I)-1a(A)-b/Formula (I)-2a (A)-b. In the present specification, thediastereomers are expressed as a compound name (A)-a and a compound name(A)-b for a compound name.

A compound obtained from an enantiomer (B) (I-I-B) having a longerelution time when Formula (I-I) is separated by chiral column resolutionis represented as Formula (I)-1a-2 (B)/Formula (I)-2a-2 (B). A compoundof Formula (I)-1a (B)/Formula (I)-2a (B) that is obtained by reductionusing the compound also includes isomers (diastereomers), which aresimilarly represented by Formula (I)-1a (B)-a/Formula (I)-2a (B)-a andFormula (I)-1a (B)-b/Formula (I)-2a (B)-b. The diastereomers areexpressed as a compound name (B)-a and a compound name (B)-b for acompound name.

In the present specification, when n=2 in Formula (I)-1a/Formula (I)-2aabove, Formula (I)-1a/Formula (I)-2a includes optical isomers. Theisomers can be separated through optical resolution using chiral columnchromatography or asymmetric synthesis by a person skilled in the artbased on conventional techniques.

<Production Method D>

<When R^(2a)≠H, R^(2b)=H, and R^(11a)=H in Formula (I)-1a Above>

<Step 1>

The compound of Formula (B-VI)a obtained in <Step 4> in (ProductionMethod B) above is subjected to substitution reaction on the isothiazolering.

<When R^(2a)=Halogen Atom>

In accordance with methods known in literatures, for example, the methoddescribed in [Organic And Biomolecular Chemistry, vol. 5 (3), pp.643-471 (2007)], a compound of Formula (B-VI)b can be produced byhalogenation reaction of the compound of Formula (B-VI)a in the presenceof a corresponding halogenating agent such asN-fluorodibenzenesulfonimide, N-chlorosuccinimide, N-bromosuccinimide,and N-iodosuccinimide in a reaction inert solvent including ahalogenated solvent such as dichloromethane and chloroform, an ethersolvent such as diethyl ether and tetrahydrofuran, an aromatichydrocarbon solvent such as toluene and benzene, and a polar solventsuch as N,N-dimethylformamide or in a mixed solvent of them at atemperature from −78° C. to a reflux temperature of the solvent.

<When R^(2a)=Cyano Group>

In accordance with methods known in literatures, for example, the methoddescribed in [Tetrahedron Letters, vol. 40 (47), pp. 8193-8195 (1999)],a compound of Formula (B-VI)b can be produced by reacting the compoundof Formula (B-VI)b (R^(2a)=I, Br) obtained in <When R^(2a)=halogen atom>in <Step 1> in (Production Method D) in the presence of a correspondingcyanating agent such as zinc cyanide and potassium ferrocyanide in thepresence of a palladium catalyst such as palladium(II) acetate, tetrakistriphenylphosphine palladium, tris(dibenzylideneacetone)dipalladium, and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), a phosphinereagent such as triphenylphosphine, tris(tert-butyl)phosphine, andtris(o-tolyl)phosphine, and an organic or inorganic base such astriethylamine, N,N-diisopropylethylamine, and potassium phosphate usinga reaction inert solvent such as toluene, xylene, N,N-dimethylformamide,and N,N-dimethylacetamide or a mixed solvent of them at a temperaturefrom 0° C. to a reflux temperature of the solvent. It can also beproduced in a similar method using tetramethylammonium chloride,tetrabutylammonium chloride, or the like in place of the phosphinereagent.

<Step 2>

The sulfur atom in the compound of Formula (B-VI)b is oxidized. Acompound of Formula (B-VII)b can be produced by reacting the compound ofFormula (B-VI)b in a similar manner to that in <Step 2> in (ProductionMethod A).

<Step 3>

The protective group P² in the compound of Formula (B-VII)b isdeprotected. A compound of Formula (I)-1a-2 can be produced by reactingthe compound of Formula (B-VII)b in a similar manner to that in <Step 6>in (Production Method B).

<Step 4>

The compound of Formula (B-VI)b is simultaneously subjected to oxidationand deprotection of the protective group P². A compound of Formula(I)-1a-2 can be produced by reacting the compound of Formula (B-VI)b ina similar manner to that in

<Step 7> in (Production Method B).

<Step 5>

The compound of Formula (I)-1a-2 is subjected to reduction. The compoundof Formula (I)-1a can be produced by reacting the compound of Formula(I)-1a-2 in a similar manner to that in <Step 3> in (Production MethodA).

(2) Next, methods for producing the compounds of Formula (IX)-1a,Formula (B-I), and Formula (B-II) will be described.

The compounds of Formula (IX)-1a and Formula (B-I) can be produced bythe methods below.

<Production Method E>

<Step 1>

A compound of Formula (E-I) is subjected to alkynylation. In accordancewith methods known in literatures, for example, the methods described in[Jikken Kagaku Koza (Experimental Chemistry Course), the fourth edition,vol. 19, Organic Synthesis I, Hydrocarbon and Halogenated Compounds, pp.318-335 (1992), Maruzen Co., Ltd.] and [WO 2008/066131 pamphlet,Reference Example 1], a compound of Formula (E-II) can be produced byreacting the compound of Formula (E-I), which is known in the art or canbe easily produced from a known compound, in the presence of acorresponding propiolic acid ester such as methyl propiolate and ethylpropiolate and copper(II) oxide using a reaction inert solvent such astoluene, xylene, N,N-dimethylformamide, and N,N-dimethylacetamide or amixed solvent of them at a temperature from 0° C. to a refluxtemperature of the solvent.

The compound of Formula (E-II) can also be produced by reaction in thepresence of an ortho ester of a corresponding propiolic acid such as3,3,3-triethoxypropyne or a corresponding propiolic acid ester such asmethyl propiolate and ethyl propiolate in the presence of copper(I)iodide or zinc bromide in the presence of a palladium catalyst such aspalladium(II) acetate, tetrakis triphenylphosphine palladium,tris(dibenzylideneacetone)dipalladium, and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), a phosphinereagent such as triphenylphosphine, tris(tert-butyl)phosphine, andtris(o-tolyl)phosphine, and an organic or inorganic base such astriethylamine, N,N-diisopropylethylamine, potassium phosphate, andpotassium carbonate using a reaction inert solvent such as toluene,xylene, N,N-dimethylformamide, and N,N-dimethylacetamide or a mixedsolvent of them at a temperature from 0° C. to a reflux temperature ofthe solvent.

<Step 2>

The compound of Formula (E-II) is hydrolyzed. In accordance with methodsknown in literatures, for example, the method described in [JikkenKagaku Koza (Experimental Chemistry Course), the fourth edition, vol.22, Organic Synthesis IV, Acid, Amino Acid, and Peptide, pp. 1-43(1992), Maruzen Co., Ltd.], a compound of Formula (E-III) can beproduced by reacting the compound of Formula (E-II) in the presence of abase such as lithium hydroxide, sodium hydroxide, potassium hydroxide,lithium carbonate, sodium carbonate, and potassium carbonate using areaction inert solvent such as water, methanol, ethanol, 2-propanol,N,N-dimethylformamide, 1,4-dioxane, and tetrahydrofuran or a mixedsolvent of them at a temperature from 0° C. to a reflux temperature ofthe solvent.

<Step 3>

The compound of Formula (E-III) is subjected to amidation reaction. Inaccordance with methods known in literatures, for example, the methoddescribed in [Jikken Kagaku Koza (Experimental Chemistry Course), thefourth edition, vol. 22, Organic Synthesis IV, Acid, Amino Acid, andPeptide, pp. 191-309 (1992), Maruzen Co., Ltd.], a compound of Formula(B-I) can be produced by reacting the compound of Formula (E-III) withaqueous ammonia or ammonia gas in the presence of a condensing agentsuch as 1,3-dicyclohexylcarbodiimide (DCC),1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (WSC—HCl),benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(BOP reagent), bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOP—Cl),2-chloro-1,3-dimethylimidazolinium hexafluorophosphate (CIP), and4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride(DMTMM) in a reaction inert solvent including a halogenated solvent suchas dichloromethane and chloroform, an ether solvent such as diethylether and tetrahydrofuran, an aromatic hydrocarbon solvent such astoluene and benzene, a polar solvent such as N,N-dimethylformamide, oran alcoholic solvent such as methanol, ethanol, and 2-propanol or in amixed solvent of them in the presence or absence of a base such astriethylamine and pyridine at a temperature from 0° C. to a refluxtemperature of the solvent. When the compound of Formula (E-III) isconverted into an acid chloride, in accordance with the methodsdescribed in [Jikken Kagaku Koza (Experimental Chemistry Course), thefourth edition, vol. 22, Organic Synthesis IV, Acid, Amino Acid, andPeptide, pp. 144-146 (1992), Maruzen Co., Ltd.] and the like, thecompound of Formula (B-I) can be produced by reacting the acid chloridein the presence of a base such as triethylamine and pyridine in areaction inert solvent including a halogenated solvent such asdichloromethane and chloroform, an ether solvent such as diethyl etherand tetrahydrofuran, an aromatic hydrocarbon solvent such as toluene andbenzene, and a polar solvent such as N,N-dimethylformamide or in a mixedsolvent of them at a temperature from 0° C. to a reflux temperature ofthe solvent.

<Step 4>

The protective group P¹ in the compound of Formula (B-I) is deprotected.A compound of Formula (E-IV) can be produced by reacting the compound ofFormula (B-I) in a similar manner to that in <Step 3> in (ProductionMethod B).

<Step 5>

The compound of Formula (E-IV) is subjected to substitution reactionwith a compound of Formula (B-V). A compound of Formula (IX)-1a can beproduced by reacting the compound of Formula (E-IV) with the compound ofFormula (B-V) in a similar manner to that in <Step 4> in (ProductionMethod B).

<Step 6>

The compound of Formula (B-I) can also be produced from the compound ofFormula (E-II). Namely, in accordance with methods known in literatures,for example, the method described in [Tetrahedron, vol. 61 (48), pp.11333-11344 (2001)], the compound of Formula (E-II) can be produced byreaction in the presence of ammonia using a reaction inert solvent suchas water, methanol, ethanol, 2-propanol, N,N-dimethylformamide,1,4-dioxane, and tetrahydrofuran or in a mixed solvent of them at atemperature from −78° C. to a reflux temperature of the solvent.

The compound of Formula (IX)-1a can also be produced by the followingmethod.

<Production Method F>

<Step 1>

A compound of Formula (F-I) is subjected to substitution reaction with acompound of Formula (B-V). A compound of Formula (F-II) can be producedby reacting the compound of Formula (F-I), which is known in the art orcan be easily produced from a known compound, with the compound ofFormula (B-V) in a similar manner to that in

<Step 4> in (Production Method B).

<Step 2>

The compound of Formula (F-II) is subjected to alkynylation. A compoundof Formula (F-III) can be produced by reacting the compound of Formula(F-II) in a similar manner to that in <Step 1> in (Production Method E).

<Step 3>

The compound of Formula (F-III) is hydrolyzed. A compound of Formula(F-IV) can be produced by reacting the compound of Formula (F-III) in asimilar manner to that in <Step 2> in (Production Method E).

<Step 4>

The compound of Formula (F-IV) is subjected to amidation reaction. Thecompound of Formula (IX)-1a can be produced by reacting the compound ofFormula (F-IV) in a similar manner to that in <Step 3> in (ProductionMethod E).

<Step 5>

The compound of Formula (IX-Ia) can also be produced from the compoundof Formula (F-III) in a similar manner to that in <Step 6> in<Production Method E>.

The compound of Formula (B-II) can also be produced by the method below.

<Production Method G>

<Step 1>

A compound of Formula (G-I) is subjected to boration reaction.

<When W=Boronic Ester>

In accordance with methods known in literatures, for example, the methoddescribed in [The Journal of Organic Chemistry, vol. 60, pp. 7508-2665(1995)], a boronic ester of Formula (G-II) can be produced by reactingthe compound of Formula (G-I), which is known in the art or can beeasily produced from a known compound, in the presence of a diboronicester such as bis(pinacolato)diboron and bis(neopentylglycolato)diboronin the presence of a palladium catalyst such as palladium(II) acetate,tetrakis triphenylphosphine palladium,tris(dibenzylideneacetone)dipalladium, and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) in thepresence or absence of a phosphine reagent such as triphenylphosphine,tris(tert-butyl)phosphine, tris(o-tolyl)phosphine, and2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl and an organic orinorganic base such as triethylamine, N,N-diisopropylethylamine, andpotassium acetate using a reaction inert solvent such as toluene,N,N-dimethylformamide, dimethyl sulfoxide, and 1,4-dioxane or a mixedsolvent of them at a temperature from 0° C. to a reflux temperature ofthe solvent. It can also be produced in a similar method usingtetramethylammonium chloride, tetrabutylammonium chloride, or the likein place of the phosphine reagent.

<When W=Boronic Acid>

In accordance with methods known in literatures, for example, the methoddescribed in [Chemische Berichte, vol. 42, p. 3090 (1909)], a boronicacid of Formula (G-II) can be produced by reacting the compound ofFormula (G-I) using a reaction inert solvent such as toluene,tetrahydrofuran, and 1,4-dioxane or a mixed solvent of them in thepresence of an alkyllithium such as n-butyllithium and sec-butyllithium,a Grignard reagent such as isopropyl magnesium chloride, or metalmagnesium, with a trialkyl borate such as trimethyl borate andtriisopropyl borate at a temperature from −78° C. to room temperature,followed by reaction with an acid such as hydrochloric acid and sulfuricacid at a temperature from 0° C. to a reflux temperature of the solvent.

<When W=trifluoroborate salt>

In accordance with methods known in literatures, for example, the methoddescribed in [Chemical Reviews, vol. 108, pp. 288-325 (2008)], atrifluoroborate salt of Formula (G-II) can be produced by reacting thecompound of Formula (G-II) (W=boronic ester or boronic acid) obtained in<When W=boronic ester or boronic acid> in <Step 1> in (Production MethodG) in the presence of potassium hydrogen difluoride (KHF₂) using areaction inert solvent such as methanol, ethanol, and water or a mixedsolvent of them at a temperature from 0° C. to a reflux temperature ofthe solvent.

<When W=Boronic Acid N-Methylimino Diacetic Acid (MIDA) Ester>

In accordance with methods known in literatures, for example, the methoddescribed in [Journal of Organometallic Chemistry, vol. 307 (1), pp. 1-6(1986)], a boronic acid N-methylimino diacetic acid (MIDA) ester ofFormula (G-II) can be produced by reacting the compound of Formula(G-II) (W=boronic acid) obtained in <When W=boronic acid> in <Step 1> in(Production Method G) in the presence of N-methyliminodiacetic acid(MIDA) using a reaction inert solvent such as benzene, toluene, xylene,and dimethyl sulfoxide or a mixed solvent of them at a temperature from0° C. to a reflux temperature of the solvent.

<Step 2>

The compound of Formula (G-II) is subjected to substitution reactionwith a compound of Formula (G-III). The compound of Formula (B-II) canbe produced by reacting the compound of Formula (G-II) with the compoundof Formula (G-III), which is known in the art or can be easily producedfrom a known compound, in a similar manner to that in <Step 1> in(Production Method C).

(3) Next, a method for producing the compound of Formula (C-I) will bedescribed.

<Production Method H>

<Step 1>

A compound of Formula (H-I) is subjected to substitution reaction with acompound of Formula (B-V). A compound of Formula (H-II) can be producedby reacting the compound of Formula (H-I), which is known in the art orcan be easily produced from a known compound, with the compound ofFormula (B-V) in a similar manner to that in

<Step 4> in (Production Method B).

<Step 2>

The compound of Formula (H-II) is subjected to boration reaction. Thecompound of Formula (C-I) can be produced by reacting the compound ofFormula (H-II) in a similar manner to that in <Step 1> in (ProductionMethod G).

<Step 3>

The compound of Formula (H-I) is subjected to boration reaction. Acompound of Formula (H-III) can be produced by reacting the compound ofFormula (H-I) in a similar manner to that in <Step 1> in (ProductionMethod G).

<Step 4>

The compound of Formula (H-III) is subjected to substitution reactionwith the compound of Formula (B-V). The compound of Formula (C-I) can beproduced by reacting the compound of Formula (H-III) with the compoundof Formula (B-V) in a similar manner to that in <Step 4> in (ProductionMethod B).

(4) Next, a method for producing the compound of Formula (C-II) will bedescribed.

<Production Method I>

<When n is 1 or 2 in Formula (C-II) Above>

The sulfur atom in a compound of Formula (G-III)a is oxidized. Acompound of Formula (1-I) (m=1 or 2) can be produced by reacting thecompound of Formula (G-III)a, which is known in the art or can be easilyproduced from a known compound, in a similar manner to that in <Step 2>in (Production Method A).

The compounds of Formula (G-III)a and Formula (I-I) are included in thecompound of Formula (C-II).

When m is 1 in Formula (I-I) above, the compound of Formula (I-I)includes optically active isomers. The isomers can be separated throughoptical resolution using column chromatography or asymmetric synthesisby a person skilled in the art based on conventional techniques. Forexample, each enantiomer can be obtained using preparativechromatography as in Step 5 in Example 1 described later.

(5) Hereinafter, the method for producing the compound of Formula (B-V)of the present invention will be described in further detail. As typicalexamples, methods for producing a compound of Formula (B-V)-II havingPartial Structural Formula (A) above and a compound of Formula (B-V)-IIIhaving Partial Structural Formula (AA)-1 above will be described.

<Production Method J>

A compound of Formula (J-I) is subjected to substitution reaction on thering.

<When V=Single Bond>

A compound of Formula (B-V)-II can be produced by reacting the compoundof Formula (J-I), which is known in the art or can be easily producedfrom a known compound, with a compound of Formula (J-II) (W² is boronicacid, a boronic ester, or a trifluoroborate salt when W¹ is a halogenatom or a trifluoromethanesulfonyloxy group, and vice versa) in asimilar manner to that in <Step 1> in (Production Method C).

<When V=Oxygen Atom>

In accordance with methods known in literatures, for example, the methoddescribed in [Tetrahedron Letters, vol. 44, pp. 3863-3865 (2003)], thecompound of Formula (B-V)-II can be produced by reacting the compound ofFormula (J-I) in the presence of a compound of Formula (J-II) (W² isboronic acid, a boronic ester, or a trifluoroborate salt when W¹ is ahydroxy group, and vice versa) in the presence of a copper catalyst suchas copper(II) acetate and copper(II) trifluoroacetate and a base such astriethylamine, N,N-diisopropylethylamine, and pyridine using a reactioninert solvent such as dichloromethane, 1,4-dioxane, tetrahydrofuran, andN,N-dimethylformamide or a mixed solvent of them at a temperature from0° C. to a reflux temperature of the solvent.

When R⁸ or R⁹ is an electron withdrawing group or the ring A′ isheteroaryl, the compound of Formula (B-V)-II can also be produced byreacting a compound of Formula (J-I) (W¹=hydroxy group) with a compoundof Formula (J-II) (W²=halogen atom) in a similar manner to that in <Step4> in (Production Method B).

The compound of Formula (MI) used in this step is known in the art orcan be easily produced from a known compound. Specifically, ahalogenated derivative can be produced from a corresponding compound inaccordance with methods known in literatures, for example, the methodsdescribed in [WO 2005/063729 pamphlet, Reference Example 1 and thelike], [WO 2008/001931 pamphlet, <Step 4A> in Reaction Scheme 2,Reference Examples 1, 54, and the like], and [WO 2009/054423 pamphlet,Production Example 37 and the like]. Furthermore, a boronic acidderivative can be produced by boration reaction of the halogenatedderivative in a similar manner to that in

<Step 1> in (Production Method G).

<Production Method J-1>

<When j=1, R³, R⁴=H, and Z=OH in Formula (B-V)-II Above>

<Step 1>

A compound of Formula (J1-I) is subjected to substitution reaction onthe ring.

<When V=Single Bond>

A compound of Formula (J1-II) can be produced by reacting the compoundof Formula (J1-I), which is known in the art or can be easily producedfrom a known compound, with a compound of Formula (J-II) in a similarmanner to that in <When V=single bond> in (Production Method J).

<When V=Oxygen Atom>

A compound of Formula (J1-II) can be produced by reacting the compoundof

Formula (J1-I) with a compound of Formula (MI) in a similar manner tothat in <When V=oxygen atom> in (Production Method J).

<Step 2>

The compound of Formula (J1-II) is subjected to reduction. In accordancewith methods known in literatures, for example, the method described in[Jikken Kagaku Koza (Experimental Chemistry Course), the fourth edition,vol. 26, Organic Synthesis VIII, Asymmetric Synthesis, Reduction, Sugar,and Labelled Compound, pp. 234-245 (1992), Maruzen Co., Ltd.], thecompound of Formula (B-V)-II-1 can be produced by reacting the compoundof Formula (J1-II) in the presence of sodium borohydride (when R″=H),diisobutyl aluminum hydride (DIBAH), lithium aluminum hydride (LAH),lithium triethoxyaluminum hydride (when R″=C₁₋₆ alkoxy group),borane-tetrahydrofuran (BH₃-THF), borane-dimethyl sulfide (BH₃-Me₂S)(when R″=OH), or the like using a reaction inert solvent including anether solvent such as diethyl ether, tetrahydrofuran,1,2-dimethoxyethane, and 1,4-dioxane, a halogenated solvent such asdichloromethane, chloroform, and 1,2-dichloroethane, or an alcoholicsolvent such as methanol and ethanol or a mixed solvent of them at atemperature from 0° C. to a reflux temperature of the solvent.

The compound of Formula (B-V)-II-1 can also be produced from acorresponding compound in accordance with methods known in literatures,for example, the methods described in [WO 2005/063729 pamphlet,Reference Examples 2, 3 and the like], [WO 2008/001931 pamphlet,Reaction Scheme 2, Reference Examples 15-19, and the like], [WO2008/130514 pamphlet, Method A, Method C, and the like], [WO 2009/048527pamphlet, Reaction Formulae 5 and 6, Example 66.6, and the like], and[WO 2009/054423 pamphlet, Production Examples 12, 24, 37, and the like].

<Production Method J-2>

A compound of Formula (J2-I) is subjected to substitution reaction onthe ring.

<When V=Single Bond>

The compound of Formula (B-V)-III can be produced by reacting thecompound of Formula (J2-I), which is known in the art or can be easilyproduced from a known compound, with a compound of Formula (J-II) in asimilar manner to that in <When V=single bond> in (Production Method J).

<When V=Oxygen Atom>

The compound of Formula (B-V)-III can be produced by reacting thecompound of Formula (J2-I) with a compound of Formula (J-II) in asimilar manner to that in <When V=Oxygen Atom> in (Production Method J).

The compound of Formula (J2-I) includes optical isomers because a carbonatom in the ring is an asymmetric carbon by bonding the carbon atom tothe linker moiety including Z. Such isomers are known in the art or canbe easily produced from a known compound. Each enantiomer can beobtained through optical resolution using column chromatography orasymmetric synthesis by a person skilled in the art based onconventional techniques. For example, the isomers are separated with anoptical resolution column, and each absolute configuration can bedetermined in accordance with [Agric. Biol. Chem., vol. 46 (10), pp.2579-2585 (1982)]. Furthermore, the enantiomers can be obtained inaccordance with the method described in [WO 2009/157418 pamphlet,Example 51 and Example 52]. Each enantiomer of Formula (B-V)-III (forexample, compounds in Example 25-5 described later) can be producedusing such an enantiomer.

<Production Method J-3>

<When j=0 and Z=OH in Formula (B-V)-III Above>

<Step 1>

A compound of Formula (J3-I) is subjected to substitution reaction onthe ring.

<When V=Single Bond>

A compound of Formula (J3-II) can be produced by reacting the compoundof Formula (J3-I), which is known in the art or can be easily producedfrom a known compound, with a compound of Formula (J-II) in a similarmanner to that in <When V=single bond> in (Production Method J).

<When V=Oxygen Atom>

A compound of Formula (J3-II) can be produced by reacting the compoundof Formula (J3-I) with a compound of Formula (J-II) in a similar mannerto that in <When

V=oxygen atom> in (Production Method J).

<Step 2>

The compound of Formula (J3-II) is subjected to reduction. The compoundof Formula (B-V)-III-1 can be produced by reacting the compound ofFormula (J3-II) with sodium borohydride, diisobutyl aluminum hydride(DIBAH), or lithium aluminum hydride (LAH) in a similar manner to thatin <Step 2> in (Production Method J-1).

The compound of Formula (B-V)-III-1 can also be produced from acorresponding compound in accordance with methods known in literatures,for example, the methods described in [WO 2005/063729 pamphlet,Reference Examples 2, 3 and the like], [WO 2008/001931 pamphlet,Reaction Scheme 2, Reference Examples 15-19, and the like], and [WO2009/054423 pamphlet, Production Examples 12, 24, 37, and the like].

(5-1) As another typical example of the compound of Formula (B-V), amethod for producing a compound of Formula (B-V)-IV having PartialStructural Formula (A1)-IV:

will be described.

<Production Method J-4>

<When the Ring a is Partial Structural Formula (A1)-IV Above, j=1, R³,R⁴=H, and Z=OH in Formula (B-V) above>

An amino alcohol of Formula (J4-I) is subjected to substitutionreaction. In accordance with methods known in literatures, for example,the method described in [WO 2006/021401 pamphlet], the compound ofFormula (B-V)-IV can be produced by reacting the compound of Formula(J4-I), which is known in the art or can be easily produced from a knowncompound, with a compound of Formula (J-II)a in the presence ofpotassium phosphate and copper iodide using a reaction inert solventincluding a polar solvent such as dimethylaminoethanol andN,N-dimethylformamide, an ether solvent such as diethyl ether,tetrahydrofuran, 1,2-dimethoxyethane, and 1,4-dioxane, or an alcoholicsolvent such as methanol and ethanol or a mixed solvent of them at atemperature from 0° C. to a reflux temperature of the solvent.

(5-2) As another typical example of the compound of Formula (B-V), amethod for producing a compound of Formula (B-V)-V having PartialStructural Formula (AA1)-V:

will be described.

<Production Method J-5>

<When the Ring a is Partial Structural Formula (AA1)-V Above (when V=anOxygen Atom), j=1, R³, R⁴=H, and Z=OH in Formula (B-V) Above>

<Step 1>

A compound of Formula (J5-I) [in Formula, R″ is a C₁₋₆ alkoxy group] isoxidized. In accordance with methods known in literatures, for example,the method described in [Journal of Organic Chemistry, vol. 43, pp. 2057(1978)], a compound of Formula (J5-II) can be produced by reacting thecompound of Formula (J5-I), which is known in the art or can be easilyproduced from a known compound, with chromium trioxide (CrO₃) in thepresence of 3,5-dimethylpyrazole using a reaction inert solvent such asmethylene chloride, 1,2-dichloroethane, acetonitrile, and benzene or amixed solvent of them at a temperature from 0° C. to a refluxtemperature of the solvent.

<Step 2>

[When the Ring Structure in Formula (J5-III) has a Double Bond(γ-hydroxy-α,β-Unsaturated Ester)]

The compound of Formula (J5-II) is subjected to reduction. A compound ofFormula (J5-III) can be produced by reacting the compound of Formula(J5-II) with sodium borohydride and cerium chloride in a similar mannerto that in <Step 2> in (Production Method J-1).

[When the Ring Structure in Formula (J5-III) is Saturated(γ-Hydroxy-α,β-Saturated ester)]

The compound of Formula (J5-II) is subjected to reduction. A compound ofFormula (J5-III) can be produced by reacting the compound of Formula(J5-II) with sodium borohydride in a similar manner to that in <Step 2>in (Production Method J-1).

<Step 3>

The compound of Formula (J5-III) is subjected to substitution reactionwith a compound of Formula (J-II)b. A compound of Formula (J5-IV) can beproduced by reacting the compound of Formula (J-II)b, which is known inthe art or can be easily produced from a known compound, with thecompound of Formula (J5-III) in a similar manner to that in <Step 4> in(Production Method B).

<Step 4>

[When the Aliphatic Ring Structure has a Double Bond(γ-Hydroxy-α,β-Unsaturated ester)]

The compound of Formula (J5-IV) is subjected to reduction. The compoundof Formula (B-V)-V can be produced by reacting the compound of Formula(J5-IV) with diisobutyl aluminum hydride (DIBAH) in a similar manner tothat in <Step 2> in

(Production Method J-1).

[When the Aliphatic Ring Structure is Saturated (γ-Hydroxy-α,β-SaturatedEster)]

The compound of Formula (J5-IV) is subjected to reduction. The compoundof Formula (B-V)-V can be produced by reacting the compound of Formula(J5-IV) with lithium aluminum hydride (LAH) or diisobutyl aluminumhydride (DIBAH) in a similar manner to that in <Step 2> in (ProductionMethod J-1).

(5-3) As another typical example of the compound of Formula (B-V), amethod for producing a compound of Formula (B-V)-VI having PartialStructural Formula (AA)-VI:

will be described.

<Production Method J-6>

<When the Ring A Is Partial Structural Formula (AA)-VI Above, j=1, R³,R⁴=H, and Z=OH in Formula (B-V) Above>

<Step 1>

A compound of Formula (J64) [in Formula, R″ is a C₁₋₆ alkoxy group] issubjected to reductive amination. In accordance with methods known inliteratures, for example, the method described in [The Journal ofOrganic Chemistry, vol. 61, pp. 3849-3862 (1996)], a compound of Formula(J6-III) can be produced by reacting the compound of Formula (J64),which is known in the art or can be easily produced from a knowncompound, with a compound of Formula (J6-II) in the presence of areducing agent such as sodium triacetoxyborohydride and sodiumcyanoborohydride in the presence or absence of a catalytic amount ofacetic acid using a reaction inert solvent such as dichloromethane,1,2-dichloroethane, tetrahydrofuran, acetonitrile, and toluene or amixed solvent of them at a temperature from 0° C. to a refluxtemperature of the solvent.

<Step 2>

The compound of Formula (J6-III) is subjected to reduction. The compoundof Formula (B-V)-VI can be produced by reacting the compound of Formula(J6-III) in a similar manner to that in <Step 2> in (Production MethodJ-1).

(3-1) The compound of Formula (C-I) can also be produced by the methodsbelow.

<Production Method H-1>

<When the ring A is Partial Structural Formula (A) above, the ring B isthe ring B′, j=1, k=0, R³, R⁴=H, and X=NR⁷ in Formula (C-I) above>

A compound of Formula (H1-I) is subjected to reductive amination. Thecompound of Formula (C-I)-II can be produced by reacting the compound ofFormula (H1-I) (the compound of Formula (H1-I) is included in thecompound of Formula (J1-II) and can be easily produced from a knowncompound as shown in <Step 1> in (Production Method J-1) above) with acompound of Formula (H1-II) (it is known in the art or can be easilyproduced from a known compound) in a similar manner to that in

<Step 1> in (Production Method J-6).

<Production Method H-2>

<When the Ring A is Partial Structural Formula (AA1):

the ring B is the ring B′, j, k=0, and X=NH in Formula (C-I) above>

A compound of Formula (H2-I) is subjected to reductive amination. Inaccordance with methods known in literatures, for example, the methoddescribed in [WO 2006/128670 pamphlet], the compound of Formula(C-I)-III can be produced by reacting the compound of Formula (H2-I) (itis known in the art or can be easily produced from a known compound asshown in <Step 1> in (Production Method J-3) above and the like) with acompound of Formula (H2-II) (it is known in the art or can be easilyproduced from a known compound) (<Step 1>).

The compound of Formula (C-I)-III can also be produced by reacting, inaccordance with methods known in literatures, for example, the methoddescribed in [WO 2006/085149 pamphlet], the compound of Formula (H2-I)with hydroxylamine hydrochloride to afford an oxime, then byhydrogenating the oxime using hydrogen and Pd—C to produce a compound ofFormula (H2-II) (<Step 2>), and by reacting the obtained compound ofFormula (H2-II) with a compound of Formula (H2-III) in accordance withmethods known in literatures, for example, the method described in [WO2005/682859 pamphlet or Journal of the American Chemical Society, vol.128 (29), pp. 9306-9307 (2006)] (<Step 3>). Z₁ in Formula (H2-III) aboveis halogen, a methanesulfonyloxy group, or a p-toluenesulfonyloxy groupin Z above.

<Step 2> above can be carried out with reference to known reactionconditions for reductive amination, for example, in [WO 2006/083454pamphlet, p. 62, Steps A and B in Preliminary Example] and [WO2010/143733 pamphlet, Reference Example 68]. <Step 3> above can becarried out in accordance with known reaction conditions forsubstitution, for example, in [WO 2010/143733 pamphlet, [0184], Step 7].

<Production Method H-3>

<When the Ring A is Partial Structural Formula (A)-V:

the ring B is the ring B′, j=1, k=0, R³, R⁴=H, and X=oxygen atom inFormula (C-I) above>

A compound of Formula (H3-I) is subjected to substitution reaction witha compound of Formula (H3-II). The compound of Formula (C-I)-V can beproduced by reacting the compound of Formula (H3-II), which is known inthe art or can be easily produced from a known compound, with thecompound of Formula (H3-I) in a similar manner to that in <Step 4> in(Production Method B) or in accordance with the method described in [WO2009/054479 pamphlet, Step 1 or Step 1′ in Production Method A1 (forexample, Step 6 in Example 41)]. For example, condensation is carriedout in a solvent at room temperature or under heating. Examples of thereagent include 1,1′-(diazocarbonyl)dipiperidine and triphenylphosphine.Examples of the solvent include an ether solvent such astetrahydrofuran.

The compound of Formula (H3-I) above is known in the art or can beeasily produced from a known compound with reference to, for example,[WO 2009/054479 pamphlet, Production Method B, C, D, or the like(paragraphs [0185] to [0264])].

Hereinafter, the methods for producing the compound of Formula (H3-I) ofthe present invention will be described in further detail.

<Production Method H-4>

<When n3=1, the broken line adjacent to the carbon atom in the n3 moietyis a double bond, and the other broken lines are single bonds in Formula(H3I) above>

<Step 1>

A compound of Formula (H4-I) is subjected to substitution reaction witha compound of Formula (H4-II) (each X₃a in Formula (H4-II) isindependently —CR_(V1a)R_(V2a)— or —NR_(V3a)—, each of R_(V1a), R_(V2a),and R_(v3a) is independently a hydrogen atom, —OH, or —NH₂, eachdefinition of Z₁ and Z₂ is the same as that of Z above, and Z₁ and Z₂are preferably a halogen atom). A compound of Formula (H4-III) can beproduced by reacting the compound of Formula (H4-I), which is known inthe art or can be easily produced from a known compound, with thecompound of Formula (H4-II) in accordance with the method described in[WO 2009/054479 pamphlet, Production Method D1-1 (for example, Step 1 inExample 41 and Step 4 in Example 104)]. For example, the condensation iscarried out in a solvent at room temperature or under heating in thepresence of a base. Examples of the base include potassium tert-butoxideand sodium hydride. Examples of the solvent include an aromatichydrocarbon solvent such as toluene.

<Step 2>

A compound of Formula (H4-IV) can be produced from the compound ofFormula (H4-III) in accordance with the method described in [WO2009/054479 pamphlet, Steps 1 to 4 in Production Method C1-1 (forexample, Steps 2 to 4 in Example 41)].

<Step 3>

The compound of Formula (H3-I)-1 can be produced from the compound ofFormula (H4-IV) in accordance with the method described in [WO2009/054479 pamphlet, Step 5 in Production Method C1-1 (for example,Step 5 in Example 41)].

<Production Method H-5>

<When the Ring A is Partial Structural Formula (A)-VI:

the ring B is a benzene ring, a linker moiety including an isothiazolylgroup and X is placed at the p-position, j=1, k=0, and R³, R⁴=H inFormula (C-I) above>

As shown in the scheme below, in accordance with Scheme I in WO2011/046851 pamphlet, pp. 8-9, a substituted benzyl bromide of Formula(1) is reacted with a suitable substituted spiropiperidine of Formula(SP) or its hydrochloric acid salt or trifluoroacetic acid salt in thepresence of a suitable base such as diisopropylethylamine and cesiumcarbonate to give a compound of Formula (4) in step 1a. The ester isproperly reduced in step 2 with diisobutylaluminum hydride, lithiumaluminum hydride, sodium borohydride, or the like to give a substitutedbenzyl alcohol of Formula (B-V). The compound of Formula (B-V) can beproperly used in, for example, (Production Method B), (Production MethodE), (Production Method F), and (Production Method H) above and(Production Method L) below. The compound of Formula (B-V) can also beobtained by reduction in step 1b instead of step 1a to give a compoundof Formula (2), followed by reaction with the compound of Formula (SP)in step 1c in the same manner as in the above.

Here, the compound of Formula (B-V) is further reacted with a phenolderivative of Formula (B-IV) by Mitsunobu reaction in step 4a in thepresence of a suitable phosphine such as triphenylphosphine andtriethylphosphine and an azodicarbonyl such as ADDP or anazodicarboxylate such as DEAD, and then the product is properly oxidizedand deprotected in steps 6a and 6b to give a compound of Formula(VI)-1a-2 (X=oxygen atom).

Another pathway may be employed. That is, the compound of Formula (B-V)is derived to a benzyl bromide of Formula (B-V′) in step 3a with asuitable brominating agent such as phosphorus tribromide, and then thebenzyl bromide is reacted with the phenol derivative of Formula (B-IV)above in step 4b to give the compound of Formula (B-VI).

The compound of Formula (B-V′) is also reacted with a compound ofFormula (H3-II) or a compound of Formula (H1-II) in step 5a/b to give acorresponding compound of Formula (C-I)-VI (X=oxygen atom or —NR₇—).Alternatively, the compound of Formula (C-I)-VI can be derived from thecompound of Formula (B-V) by oxidation with a suitable oxidizing agentsuch as Dess-Martin reagent to give an aldehyde of Formula (5) in step3b, followed by oxidative amination with a compound of Formula (H1-II)in step 5c. The compound of Formula (C-I)-VI (X=oxygen atom or —NR₇—)can also be derived from the compound of Formula (B-V) by directMitsunobu reaction with a compound of Formula (H3-II) in step 5d.

The compound of Formula (C-I)-VI is reacted with a compound of Formula(C-II) in step 7 to give a compound of Formula (VI)-1a-2 (X=oxygen atomor —NR₇—).

A final compound of Formula (VI)-1a can be produced by reduction of theobtained compound of Formula (VI)-1a-2 in a similar manner to that in<Step 3> in (Production Method A).

Through the synthetic route shown below, the compound of Formula (B-VI)can also be obtained using a known or suitable benzyl bromide derivativeto give an intermediate, followed by reaction with a substitutedspiropiperidine of Formula (SP). Each definition of substituents andreference signs is the same as in the above.

In particular, a method for producing a compound of Formula (B-V) whereX₁ is —N(Rz)CH₂— can be with reference to WO 2011/064851 pamphlet, pp.10-11. In accordance with Scheme II in the literature, a protectedpiperidine-4-carboaldehyde is reacted with a phenylhydrazine that may besubstituted at the 2-position and/or 4-position to give a substitutedspiro[indoline-3,4′-piperidine]. The product is, as necessary, furtheralkylated, and then is deprotected to give the compound of Formula (SP)suited for the present invention.

WO 2011/046851 pamphlet discloses in pp. 29-31, as specific knowncompounds of Formula (B-V) suitably used for Production Method U of thepresent invention,(4-(spiro[inden-1,4′-piperidin]-1′-ylmethyl)phenyl)methanol as well as[3-chloro-4-(spiro[inden-1,4′-piperidin]-1′-ylmethyl)phenyl]methanol,[2-methoxy-4-(spiro[inden-1,4′-piperidin]-1′-ylmethyl)phenyl]methanol,[3-fluoro-4-(spiro[inden-1,4′-piperidin]-1′-ylmethyl)phenyl]methanol,[4-(spiro[inden-1,4′-piperidin]-1′-ylmethyl)-3-(trifluoromethyl)phenyl]methanol,[3-chloro-4-[(1-methylspiro[indolin-3,4′-piperidin]-1′-yl)methyl]phenyl]methanol,[4-(spiro[indan-1,4′-piperidin]-1′-ylmethyl)-3-(trifluoromethyl)phenyl]methanol,and [4-(spiro[indan-1,4′-piperidin]-1′-ylmethyl)phenyl]methanol.

As other usable compounds of Formula (B-V′), WO 2011/046851 pamphletalso discloses, in pp. 31-32, corresponding bromomethyl derivatives asPrep No. 56-61.

Hereinbefore, the method for producing a compound substituted with anisothiazole ring at the p position with respect to the hetero atom X hasbeen described. Furthermore, an m-isomer that can be properly obtainedor synthesized is used in place of the starting material of Formula (1)or Formula (2) to produce a corresponding compound substituted with theisothiazole ring at the m position with respect to the hetero atom X ina similar manner.

<Production Method H-5a>

It can be understood that another substituted spiropiperidine of Formula(SP′) is used in place of the substituted spiropiperidine of Formula(SP) in each production route in (Production Method H-5) to give eachcompound of Formula (B-Va), Formula (B-Va′), Formula (C-1)-VIa, Formula(B-VIa), and Formula (VIa)-1a-2 having the moiety of Formula (SP′) thatreplaces the moiety of Formula (SP) in each compound of Formula (B-V),Formula (B-V′), Formula (C-1)-VI, Formula (B-VI), and Formula (VI)-1a-2.

Furthermore, each compound of Formula (B-V), Formula (B-V′), Formula(B-Va), and Formula (B-Va') described in (Production Method H-5) and(Production Method H-5a) can be used as the compound of Formula (B-V) in(Production Method B), (Production Method E), (Production Method F), or(Production Method H) above, (Production Method L) below, or the like ineach step (for example, in <Step 4> in (Production Method B)).

<Production Method H-5b>

In place of the starting material of Formula (1) or Formula (2) used insteps 1a, 1b, and 1c in (Production Method H-5) or (Production MethodH-5a), in accordance with the description of scheme I or scheme III inpp. 5 to 10 in WO 2011/066183 pamphlet, a correspondingbromomethyl-heteroarylcarboxylic acid derivative of Formula (1) or amethyl alcohol of bromomethyl-heteroaryl of Formula (2):

(where each definition of Z₁, Z₂, and Z₃ is the same as that in Formula(A2) IV described in the aspect [1-13-e-3]) is used to produce thecompound in the aspect [1-13-e-8] or [1-13-e-8a] having a 5-memberedheteroaryl in the molecule.

(6) The compound of Formula (I)-1a can also be produced by the methodsbelow.

<Production Method K>

<When the ring A is Partial Structural Formula (AA)-1 above (that isFormula (III)-1a1), X=oxygen atom, R^(2b)=H, and R^(11a)=H in Formula(I)-1a above>

<Step 1>

A compound of Formula (H-III)a is subjected to substitution reactionwith a compound of Formula (K-I). A compound of Formula (K-II) can beproduced by reacting the compound of Formula (H-III)a obtained in <Step3> in (Production Method H) above with the compound of Formula (K-I),which is known in the art or can be easily produced from a knowncompound, in a similar manner to that in <Step 4> in (Production MethodB).

<Step 2>

The compound of Formula (K-II) is subjected to substitution reactionwith a compound of Formula (I-I)a. A compound of Formula (K-III) can beproduced by reacting the compound of Formula (K-II) with the compound ofFormula (I-I)a in a similar manner to that in <Step 1> in (ProductionMethod C).

<Step 3>

The compound of Formula (K-III) is subjected to substitution reactionwith a compound of Formula (J-II).

<When V=Single Bond>

A compound of Formula (III)-1a1-2 can be produced by reacting thecompound of Formula (K-III) with the compound of Formula (J-II) in asimilar manner to that in <Step 1> in (Production Method C).

<When V=Oxygen Atom>

In accordance with methods known in literatures, for example, the methoddescribed in [Tetrahedron Letters, vol. 49, pp. 1851-1855 (2008)], acompound of Formula (III)-1a1-2 can be produced by reacting the compoundof Formula (K-III) in the presence of the compound of Formula (J-II) inthe presence of a copper catalyst such as copper(I) iodide, copper(I)bromide, copper(I) chloride, and copper(I) oxide, a base such aspotassium phosphate, potassium carbonate, and sodium tert-butoxide, andan additive such as 1-butylimidazole, 1-methylimidazole, and2,2′-bipyridine using a reaction inert solvent such as toluene, xylene,1,4-dioxane, and N-methylpyrrolidone or a mixed solvent of them at atemperature from 0° C. to a reflux temperature of the solvent.

In accordance with other methods known in literatures, for example, themethod described in [Journal of the American Chemical Society, vol. 121,pp. 4369-4378 (1999)], the compound of Formula (III)-1a1-2 can also beproduced by reacting the compounds of Formula (K-III) and Formula (J-II)in the presence of a palladium catalyst such as palladium(II) acetate,tetrakis triphenylphosphine palladium,tris(dibenzylideneacetone)dipalladium,bis(dibenzylideneacetone)palladium, and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), a phosphinereagent such as (2-biphenyl)di-(tert-butyl)phosphine,2-di-(tert-butyl)-2′-(N,N-dimethylamino)biphenyl, and2-dicyclohexyl-2′-(N,N-dimethylamino)biphenyl, and a base such aspotassium phosphate, sodium hydride, and sodium tert-butoxide using areaction inert solvent such as dichloromethane, 1,4-dioxane,tetrahydrofuran, toluene, and N,N-dimethylformamide or a mixed solventof them at a temperature from 0° C. to a reflux temperature of thesolvent.

<Step 4>

The compound of Formula (III)-1a1-2 is subjected to reduction. Thecompound of Formula (III)-1a1 can be produced by reacting the compoundof Formula (III)-1a1-2 in a similar manner to that in <Step 3> in(Production Method A).

The compound of Formula (K-I) includes optical isomers because a carbonatom is an asymmetric carbon by bonding the carbon atom to Z. As withFormula (J2-I) above, such isomers are known in the art or can be easilyproduced from a known compound. Each enantiomer can be obtained throughoptical resolution using column chromatography or asymmetric synthesisby a person skilled in the art based on conventional techniques (forexample, (1S)-4-bromo-2,3-dihydro-1H-inden-1-ol). Each enantiomer ofFormula (K-II), Formula (K-III), Formula (III)-1a1-2, and Formula(III)-1a1 (for example, compounds in Example 23-3, Example 23-4, Example23-5, and Example 23 described later) can be produced using such anenantiomer.

<Production Method L>

<When R^(2b)=H and R^(11a)=H in Formula (I)-1a>

<Step 1>

The sulfur atom of a compound of Formula (B-II) is oxidized. A compoundof Formula (L-I) can be produced by reacting the compound of Formula(B-II) in a similar manner to that in <Step 2> in (Production Method A).

<Step 2>

The compound of Formula (L-I) is subjected to reduction. A compound ofFormula (L-II) can be produced by reacting the compound of Formula (L-I)in a similar manner to that in <Step 3> in (Production Method A).

<Step 3>

The compound of Formula (L-III) is protected with a protective group P³.A compound of Formula (L-III) can be produced by reacting the compoundof Formula (L-II) in a similar manner to that in <Step 2> in (ProductionMethod B).

<Step 4>

The protective group P¹ in the compound of Formula (L-III) isdeprotected. A compound of Formula (L-IV) can be produced by reactingthe compound of Formula (L-III) in a similar manner to that in <Step 3>in (Production Method B).

<Step 5>

The compound of Formula (L-IV) is subjected to substitution reactionwith a compound of Formula (B-V). A compound of Formula (L-V) can beproduced by reacting the compound of Formula (L-IV) in a similar mannerto that in <Step 4> in (Production Method B).

<Step 6>

The protective group P³ in the compound of Formula (L-V) is deprotected.The compound of Formula (I)-1a can be produced by reacting the compoundof Formula (L-V) in a similar manner to that in <Step 3> in (ProductionMethod B).

<Production Method L-1>

<When X=oxygen atom in Formula (I) above>

<Step 1>

A compound of Formula (G-II) can be produced by reaction in a similarmanner to that in <Step 1> in (Production Method G).

<Step 2>

A compound of Formula (L-I)a can be produced by reaction in a similarmanner to that in <Step 2> in (Production Method G).

<Step 3>

A compound of Formula (L-II)a can be produced by reaction in a similarmanner to that in <Step 2> in (Production Method L).

<Step 4>

A compound of Formula (L-III)a can be produced by reaction in a similarmanner to that in <Step 3> in (Production Method L).

<Step 5>

A compound of Formula (L-IV)a can be produced by reaction in a similarmanner to that in <Step 4> in (Production Method L).

<Step 6>

A compound of Formula (L-V)a can be produced by reaction in a similarmanner to that in <Step 5> in (Production Method L).

<Step 7>

The compound of Formula (I)-1a/Formula (I)-2a can be produced byreaction in a similar manner to that in <Step 6> in (Production MethodL).

<Production Method M>

(When W=halogen atom and n=2 in Formula)

<Step 1>

A compound of Formula (C-I) is reacted. In accordance with methods knownin literatures, for example, the method described in [TetrahedronLetters, vol. 26 (22), pp. 2667-2670 (1985)], a compound of Formula(M-I) can be produced by reacting the compound of Formula (C-I) above inthe presence of a palladium catalyst such as palladium diacetate,tetrakis triphenylphosphine palladium, and tris dibenzylideneacetonedipalladium and a base such as potassium carbonate, silver carbonate,and tributylamine using a reaction inert solvent such as acetonitrile,dioxane, tetrahydrofuran, benzene, toluene, dimethyl sulfoxide, andN,N-dimethylformamide or a mixed solvent of them at a temperature fromroom temperature to a reflux temperature of the solvent.

<Step 2>

The compound of Formula (M-I) is reacted. In accordance with methodsknown in literatures, for example, the method described in [OrganicLetters, vol. 7 (22), pp. 5067-5069 (2005)], a compound of Formula(M-II) can be produced by reacting the compound of Formula (M-I) in thepresence of a sulfur reagent such as sodium sulfite using a reactioninert solvent such as ethanol and water or a mixed solvent of them at atemperature from room temperature to a reflux temperature of the solventor at high temperature and high pressure using a microwave reactionapparatus.

<Step 3>

The compound of Formula (M-II) is reacted. In accordance with methodsknown in literatures, for example, the method described in [OrganicLetters, vol. 7 (22), pp. 5067-5069 (2005)], a compound of Formula(M-III) can be produced by reacting the compound of Formula (M-II) inthe presence of a chlorinating reagent such as phosphorus pentachlorideusing a reaction inert solvent such as methylene chloride and DMF or amixed solvent of them at a temperature from room temperature to a refluxtemperature of the solvent and then by stopping the reaction withaqueous ammonia.

<Step 4>

The compound of Formula (M-III) is protected with a protective group P³.A compound of Formula (M-IV) can be produced by reacting the compound ofFormula (M-III) in a similar manner to that in <Step 2> in (ProductionMethod B).

<Step 5>

The compound of Formula (M-II) is reacted. In accordance with methodsknown in literatures, for example, the method described in [OrganicLetters, vol. 7 (22), pp. 5067-5069 (2005)], a compound of Formula(M-IV) can be produced by reacting the compound of Formula (M-II) in thepresence of a chlorinating reagent such as phosphorus pentachlorideusing a reaction inert solvent such as methylene chloride and DMF or amixed solvent of them at a temperature from room temperature to a refluxtemperature of the solvent and then by stopping the reaction with aprotected secondary amine such as benzylamine and tosylamine.

<Step 6>

<When R^(2b)≠hydrogen atom>

The compound of Formula (M-IV) is subjected to substitution reaction. Inaccordance with methods known in literatures, for example, the methoddescribed in [Jikken Kagaku Koza (Experimental Chemistry Course), thefifth edition, vol. 16, Synthesis of Organic Compound IV, Carboxylicacid, Amino acid, and Peptide, pp. 1-70 (2005), Maruzen Co., Ltd.], acompound of Formula (M-V) can be produced by reacting the compound ofFormula (M-IV) with, for example, a halogenated alkyl of R^(2b)X in thepresence of a base such as sodium ethoxide, sodium methoxide, sodiumhydride, lithium hydride, lithium hydroxide, sodium hydroxide, potassiumhydroxide, lithium carbonate, sodium carbonate, and potassium carbonateusing a reaction inert solvent such as ethanol, water,N,N-dimethylformamide, 1,4-dioxane, and tetrahydrofuran or a mixedsolvent of them at a temperature from 0° C. to a reflux temperature ofthe solvent.

<Step 7>

The compound of Formula (M-V) is subjected to ring formation reaction.In accordance with methods known in literatures, for example, the methoddescribed in [Organic Letters, vol. 7 (22), pp. 5067-5069 (2005)], acompound of Formula (M-VI) can be produced by reacting the compound ofFormula (M-V) in the presence of sodium methoxide, sodium ethoxide, orthe like using a reaction inert solvent such as methanol and ethanol ora mixed solvent of them at a temperature from room temperature to areflux temperature of the solvent.

<Step 8>

The protective group P³ in the compound of Formula (M-VI) isdeprotected. The compound of Formula (I)-1a can be produced by reactionin a similar manner to that in <Step 3> in (Production Method B).

(7) The methods for producing the compound of Formula (I)-1b of thepresent invention will be described below.

<Production Method N>

(When n=2 in Formula)

<Step 1>

A compound of Formula (N-I) can be produced by reacting the compound ofFormula (H-II) above (Y=protected imino group (—NP¹ ₂)) in a similarmanner to that in <Step 3> in (Production Method B).

<Step 2>

The compound of Formula (N-I) is reacted. In accordance with methodsknown in literatures, for example, the method described in [Chemical &Pharmaceutical Bulletin, vol. 43 (5), pp. 820-841 (1995)], a compound ofFormula (N-III) can be produced by substitution reaction of the compoundof Formula (N-I) in the presence of a compound of Formula (N-II), whichis known in the art or can be easily produced from a known compound, inthe presence or absence of a base such as diisopropylethylamine,triethylamine, pyridine, sodium hydride, sodium hydroxide, potassiumcarbonate, and cesium carbonate in a reaction inert solvent including ahalogenated solvent such as dichloromethane and chloroform, an ethersolvent such as diethyl ether and tetrahydrofuran, an aromatichydrocarbon solvent such as toluene and benzene, and a polar solventsuch as N,N-dimethylformamide or in a mixed solvent of them at atemperature from 0° C. to a reflux temperature of the solvent.

<Step 3>

The compound of Formula (N-III) is reacted. In accordance with methodsknown in literatures, for example, the method described in [WO2007/110337 pamphlet], each compound of Formula (N-IV) (n=0, 1, or 2)can be produced by reacting the compound of Formula (N-III), forexample, in the presence of a sulfur reagent such as carbamic acidn-(chlorosulfonyl)-1,1-dimethylethyl ester and in the presence orabsence of a base such as diisopropylethylamine, triethylamine,pyridine, sodium hydride, sodium hydroxide, potassium carbonate, andcesium carbonate in a reaction inert solvent including a halogenatedsolvent such as dichloromethane and chloroform, an ether solvent such asdiethyl ether and tetrahydrofuran, an aromatic hydrocarbon solvent suchas toluene and benzene, and a polar solvent such asN,N-dimethylformamide or in a mixed solvent of them at a temperaturefrom 0° C. to a reflux temperature of the solvent.

<Step 4>

The compound of Formula (N-IV) is deprotected. A compound of Formula(N-V) can be produced by reaction in a similar manner to that in <Step3> in (Production Method B).

<Step 5>

The compound of Formula (N-V) is hydrolyzed. A compound of Formula(N-VI) can be produced by reaction in a similar manner to that in <Step2> in (Production Method E).

<Step 6>

The compound of Formula (N-VI) is subjected to ring formation reaction.The compound of Formula (I)-1b can be produced by reaction in a similarmanner to that in <Step 3> in (Production Method E) (in the absence ofammonia).

<Step 7>

The compound of Formula (N-V) is subjected to ring formation reaction.The compound of Formula (I)-1b can be produced by reaction in a similarmanner to that in

<Step 7> in (Production Method M).

The compounds of Formula (II)-1b and Formula (III)-1b above are includedin the compound of Formula (I)-1b in (Production Method N) and can beproduced by a similar production method, and these compounds of Formula(I)-1b are included in the compound of Formula (I).

<Production Method O>

(When n=2 in Formula)

<Step 1>

A compound of Formula (O-I) is reacted. A compound of Formula (O-II) canbe produced by reacting the compound of Formula (O-I), which is known inthe art or can be easily produced from a known compound, with a compoundof Formula (N-II) in a similar manner to that in <Step 2> in (ProductionMethod N).

<Step 2>

The compound of Formula (O-II) is reacted. A compound of Formula (O-III)can be produced by reaction in a similar manner to that in <Step 3> in(Production Method N).

<Step 3>

The compound of Formula (O-III) is deprotected. A compound of Formula(O-VI) can be produced by reaction in a similar manner to that in <Step3> in (Production Method B).

<Step 4>

The compound of Formula (O-VI) is subjected to ring formation reaction.A compound of Formula (O-V) can be produced by reaction in a similarmanner to that in <Step 7> in (Production Method M).

<Step 5>

The protective group P¹ in the compound of Formula (O-V) is deprotected.A compound of Formula (O-VI) can be produced by reaction in a similarmanner to that in <Step 3> in (Production Method B).

<Step 6>

The compound of Formula (O-VI) is subjected to substitution reactionwith a compound of Formula (B-V). A compound of Formula (O-VII) can beproduced by reaction in a similar manner to that in <Step 4> in(Production Method B).

<Step 7>

The protective group P³ in the compound of Formula (O-VII) isdeprotected. The compound of Formula (I)-1b can be produced by reactionin a similar manner to that in <Step 3> in (Production Method B).

The compounds of Formula (II)-1b and Formula (III)-1b above are includedin the compound of Formula (I)-1b in (Production Method O) and can beproduced by a similar production method, and these compounds of Formula(I)-1b are included in the compound of Formula (I).

(7-1) The compounds of Formula (O-V) and Formula (O-VI) can also beproduced by the method below.

<Production Method P>

(When n=2 in Formula)

<Step 1>

A compound of Formula (P-I) is subjected to ring formation reaction. Acompound of Formula (P-II) can be produced by reacting the compound ofFormula (P-I) that can be produced in accordance with methods known inliteratures, for example, the method described in [Bioorganic &Medicinal Chemistry, vol. 16 (7), pp. 3550-3556 (2008)] in a similarmanner to that in <Step 7> in (Production Method M).

<Step 2>

The compound of Formula (P-II) is subjected to substitution reactionwith a compound of Formula (G-II). [When W=halogen in Formula] Thecompound of Formula (O-V) can be produced by using the compound ofFormula (P-II) and the compound of Formula (G-II) above in accordancewith methods known in literatures, for example, the method described in[WO 2007/067615 pamphlet]. [When W=boronic acid or boronic ester inFormula] The compound of Formula (O-V) can be produced by using thecompound of Formula (P-II) and the compound of Formula (G-II) above inaccordance with methods known in literatures, for example, the methoddescribed in [Bioorganic & Medicinal Chemistry, vol. 14 (17), pp.5833-5849 (2006)].

<Step 3>

The compound of Formula (P-II) is subjected to substitution reactionwith a compound of Formula (H-III). The compound of Formula (O-VI) canbe produced by reacting the compound of Formula (P-II) with the compoundof Formula (H-III) above in a similar manner to that in <Step 2> in(Production Method P).

(7-2) The compound of Formula (O-VII) can also be produced by the methodbelow.

<Production Method Q>

A compound of Formula (C-I) that is easily obtained from a knowncompound by the method in (Production Method H) is subjected tosubstitution reaction with a compound of Formula (P-II). The compound ofFormula (O-VII) can be produced by reaction in a similar manner to thatin <Step 2> in (Production Method P).

(8) The method for producing the compound of Formula (I)-1c of thepresent invention will be described below.

<Production Method R>

<When R^(2a)=R^(2b)=H, R^(12b)=H, alkyl, alkenyl, or alkynyl in Formula(I)-c above>

(In Formula, n=2 and Y=formyl group or COR^(11a) group)

<Step 1>

A compound of Formula (H-II) is reacted with a compound of Formula(R-I). In accordance with methods known in literatures, for example, themethod described in [Synlett, vol. 5, pp. 843-838 (2005)], a compound ofFormula (R-II) can be produced by reacting the compound of Formula(H-II) that is easily obtained from a known compound by the method in<Step 1> in (Production Method H) with the compound of Formula (R-I) inthe presence of a base such as hexamethyldisilazane lithium andpotassium tert-butoxide, diethyl chlorophosphate, and the like in areaction inert solvent including an ether solvent such as diethyl etherand tetrahydrofuran, an aromatic hydrocarbon solvent such as toluene andbenzene, and a polar solvent such as N,N-dimethylformamide or in a mixedsolvent of them at a temperature from −78° C. to a reflux temperature ofthe solvent.

<Step 2>

The compound of Formula (R-II) is reacted. In accordance with methodsknown in literatures, for example, the method described in [HeterocyclicCommunications, vol. 3 (1), pp. 19-22 (1995)], a compound of Formula(R-III) can be produced by reacting the compound of Formula (R-II) inthe presence of a malonic acid ester and a base such as sodium hydride,potassium tert-butoxide, sodium methoxide, and sodium methoxide in areaction inert solvent including an ether solvent such as diethyl etherand tetrahydrofuran, an aromatic hydrocarbon solvent such as toluene andbenzene, and a polar solvent such as N,N-dimethylformamide or in a mixedsolvent of them at a temperature from 0° C. to a reflux temperature ofthe solvent.

<Step 3>

The compound of Formula (R-III) is reacted. In accordance with methodsknown in literatures, for example, the method described in [Chemical &Pharmaceutical Bulletin, vol. 33 (12), pp. 5316-5327 (1985)], a compoundof Formula (R-IV) can be produced by substitution reaction in thepresence of the compound of Formula (R-III) in the presence or absenceof sodium chloride in a reaction inert solvent including a polar solventsuch as dimethyl sulfoxide and N,N-dimethylformamide or in a mixedsolvent of them at a temperature from 0° C. to a reflux temperature ofthe solvent.

<Step 4>

The protective group P¹ in the compound of Formula (R-IV) isdeprotected. A compound of Formula (R-V) can be produced by reaction ina similar manner to that in <Step 3> in (Production Method B).

<Step 5>

The compound of Formula (R-V) is subjected to ring formation reaction.The compound of Formula (I)-1c can be produced by reaction in a similarmanner to that in <Step 7> in (Production Method M).

The compounds of Formula (II)-1c and Formula (III)-1c above are includedin the compound of Formula (I)-1c in (Production Method R) and can beproduced by a similar production method, and these compounds of Formula(I)-1c are included in the compound of Formula (I). Similarly, in theproduction methods in (Production Method S) or later, the compounds ofFormula (II)-1c and Formula (III)-1c are included in the compound ofFormula (I)-1c and can be produced by a similar production method, andthese compounds of Formula (I)-1c are included in the compound ofFormula (I).

<Production Method S>

<When R^(2a) and/or R^(2b)≠H and R^(12b)=H in Formula (I)-1c Above>

(When n=2 in Formula)

<Step 1>

A compound of Formula (R-IV) is subjected to substitution reaction. Acompound of Formula (S-I) can be produced by reaction in a similarmanner to that in <Step 6> in

(Production Method M).

<Step 2>

The protective group P¹ in the compound of Formula (S-I) is deprotected.A compound of Formula (S-II) can be produced by reaction in a similarmanner to that in <Step 3> in (Production Method B).

<Step 3>

The compound of Formula (S-II) is subjected to ring formation reaction.The compound of Formula (I)-1c can be produced by reaction in a similarmanner to that in

<Step 7> in (Production Method M).

<Production Method T>

<When R^(12b)=H, alkyl, alkenyl, or alkynyl in Formula (I)-1c above>

(In Formula, n=2 and Y=formyl group or COR^(11a) group)

<Step 1>

A compound of Formula (G-I) is reacted. A compound of Formula (T-I) canbe produced by reacting a compound of Formula (G-I), which is known inthe art or can be easily produced from a known compound, with a compoundof Formula (R-I) in a similar manner to that in <Step 1> in (ProductionMethod R).

<Step 2>

The compound of Formula (T-I) is reacted. A compound of Formula (T-II)can be produced by reaction in a similar manner to that in <Step 2> in(Production Method R).

<Step 3>

The compound of Formula (T-II) is reacted. A compound of Formula (T-III)can be produced by reaction in a similar manner to that in <Step 3> in(Production Method R).

<Step 4>

The protective group P² in the compound of Formula (T-III) isdeprotected. A compound of Formula (T-IV) can be produced by reaction ina similar manner to that in <Step 3> in (Production Method B).

<Step 5>

The compound of Formula (T-IV) is subjected to ring formation reaction.A compound of Formula (T-V) can be produced by reaction in a similarmanner to that in <Step 7> in (Production Method M).

<Step 6>

The compound of Formula (T-V) is protected with a protective group P³. Acompound of Formula (T-VI) can be produced by reacting the compound ofFormula (T-V) in a similar manner to that in <Step 2> in (ProductionMethod B).

<Step 7>

The protective group P¹ in the compound of Formula (T-VI) isdeprotected. A compound of Formula (T-VII) can be produced by reactionin a similar manner to that in <Step 3> in (Production Method B).

<Step 8>

The compound of Formula (T-VII) is subjected to substitution reactionwith a compound of Formula (B-V). A compound of Formula (T-VIII) can beproduced by reaction in a similar manner to that in <Step 4> in(Production Method B).

<Step 9>

The protective group P³ in the compound of Formula (T-VIII) isdeprotected. The compound of Formula (I)-1c can be produced by reactionin a similar manner to that in <Step 3> in (Production Method B).

(8-1) The compound of Formula (I)-1c or Formula (I)-1f can also beproduced by the method below.

<Production Method U>

<When J₁=J_(1a)=CR^(11a), J₂=CR^(12a)R^(12b), and h=1 to 3 in Formula(I) Above, that is, In the Case of Formula (I)-1c or Formula (I)-1f>

(In Formula, n=2 and Y=Halogen)

<Step 1>

A compound of Formula (G-II) is reacted. In accordance with methodsknown in literatures, for example, the method described in [Journal ofOrganic Chemistry, vol. 49 (16), pp. 2922-2925 (1984)], a compound ofFormula (U-II) can be produced by reacting a compound of Formula (G-II),which is known in the art or can be easily produced from a knowncompound, with various cyclic ethers of Formula (G-I) (for example,ethylene oxide, oxetane, and tetrahydrofuran) in the presence of a basesuch as n-butyllithium and Grignard reagent, and a Lewis acid such asboron trifluoride diethyl ether complex (BF₃-Et₂O) in a reaction inertsolvent including an ether solvent such as diethyl ether andtetrahydrofuran, an aromatic hydrocarbon solvent such as toluene andbenzene, and a polar solvent such as N,N-dimethylformamide or in a mixedsolvent of them at a temperature from 0° C. to a reflux temperature ofthe solvent.

<Step 2>

The compound of Formula (U-II) is reacted. In accordance with methodsknown in literatures, for example, the method described in [JikkenKagaku Koza (Experimental Chemistry Course), the fifth edition, vol. 13,Synthesis of Organic Compound I, Hydrocarbon and Halide, pp. 374-420(2004), Maruzen Co., Ltd.], a compound of Formula (U-III) can beproduced by reacting the compound of Formula (U-II) in the presence of ahalogenating agent such as phosphorus tribromide using a reaction inertsolvent such as diethyl ether and 1,4-dioxane or a mixed solvent of themat a temperature from 0° C. to a reflux temperature of the solvent.

<Step 3>

The compound of Formula (U-III) is reacted. In accordance with methodsknown in literatures, for example, the method described in [JustusLiebigs Annalen der Chemie, vol. 586, pp. 158-164 (1954)], a compound ofFormula (U-IV) can be produced by reaction in the presence of thecompound of Formula (U-III) in the presence of a sulfur agent such assodium sulfite, potassium sulfite, sodium disulfite, and thiourea in areaction inert solvent including an alcoholic solvent such as methanoland ethanol and water or in a mixed solvent of them at a temperaturefrom 0° C. to a reflux temperature of the solvent.

<Step 4>

The compound of Formula (U-II) is reacted. In accordance with, forexample, the method described in [Organic Reaction, vol. 42 (1992)], acompound of Formula (U-IV) can be produced by reacting the compound ofFormula (U-II) with thioacetic acid in the presence of anorganophosphorus compound such as triphenylphosphine and an azo compoundsuch as an azodicarboxylic acid ester and azodicarboxylic amide in areaction inert solvent including a halogenated solvent such asdichloromethane and chloroform, an ether solvent such as diethyl etherand tetrahydrofuran, an aromatic hydrocarbon solvent such as toluene andbenzene, and a polar solvent such as N,N-dimethylformamide and dimethylsulfoxide or in a mixed solvent of them at a temperature from 0° C. to areflux temperature of the solvent to afford a compound and by reactingthe compound with chlorine in acetic acid as a solvent in accordancewith, for example, the method described in [Canadian Journal ofChemistry, vol. 62 (3), pp. 610-614 (1984)].

<Step 5>

[When X₄₌OH or a salt such as ONa and OK]

The compound of Formula (U-III) is reacted. A compound of Formula (U-IV)can be produced by reaction in a similar manner to that in <Step 3> in(Production Method M).

[When X₄=Cl]

The compound of Formula (U-III) is reacted. A compound of Formula (U-IV)can be produced by reaction in a similar manner to that in <Step 3> in(Production Method M) except that the halogenation step is excluded.

<Step 6>

The compound of Formula (U-IV) is protected with a protective group P³.A compound of Formula (U-V) can be produced by reacting the compound ofFormula (U-IV) in a similar manner to that in <Step 2> in (ProductionMethod B).

<Step 7>

The compound of Formula (U-V) is reacted. For example, when R^(11a)≠Hand Y₂=bromo, in accordance with methods known in literatures, forexample, the method described in [Journal of Organic Chemistry, vol. 57(10), pp. 2967-2970 (1992)], a compound of Formula (U-VI) can beproduced by reacting the compound of Formula (U-V) with2-bromopropanedioic acid-1,3-diethyl ester as a brominating agent at atemperature from 0° C. to a reflux temperature of the solvent. WhenR^(11a)=H and Y₂=halogen such as chloro and bromo, in accordance with,for example, the method described in [Jikken Kagaku Koza (ExperimentalChemistry Course), the fifth edition, vol. 13, Synthesis of OrganicCompound I, Hydrocarbon and Halide, pp. 374-420 (2004), Maruzen Co.,Ltd.], a compound of Formula (U-VI) can be produced by reaction in thepresence of a halogenating agent such as N-chlorosuccinimide andN-bromosuccinimide and α,α′-azobisisobutyronitrile (AIBN) using areaction inert solvent such as carbon tetrachloride and chloroform or amixed solvent of them at a temperature from 0° C. to a refluxtemperature of the solvent.

<Step 8>

The compound of Formula (U-VI) is subjected to substitution reactionwith a carboxylic acid methyl ester. In accordance with, for example,the method described in [Tetrahedron, vol. 65 (28), pp. 5462-5471(2009)], a compound of Formula (U-VIII) can be produced by using thecompound of Formula (U-VI), indium bromide (InBr₃), and a silyl enolateof Formula (U-VIII).

<Step 9>

The protective group P³ in the compound of Formula (U-IX) isdeprotected. A compound of Formula (U-X) can be produced by reaction ina similar manner to that in <Step 3> in (Production Method B).

<Step 10>

The compound of Formula (U-X) is subjected to ring formation reaction. Acompound of Formula (U-XI) can be produced by reaction in a similarmanner to that in <Step 7> in (Production Method M).

<Step 11>

The compound of Formula (U-XI) is protected with a protective group P⁴.A compound of Formula (U-XII) can be produced by reacting the compoundof Formula (U-XI) in a similar manner to that in <Step 2> in (ProductionMethod B).

<Step 12>

The protective group P¹ in the compound of Formula (U-XII) isdeprotected. A compound of Formula (U-XIII) can be produced by reactionin a similar manner to that in <Step 3> in (Production Method B).

<Step 13>

The compound of Formula (U-XIII) is subjected to substitution reactionwith a compound of Formula (B-V). A compound of Formula (U-XIV) can beproduced by reaction in a similar manner to that in <Step 4> in(Production Method B).

<Step 14>

The protective group P⁴ in the compound of Formula (U-XIV) isdeprotected. The compound of Formula (I)-1c (when h2=0) or Formula(I)-1f (when h2=1 or 2) can be produced by reaction in a similar mannerto that in <Step 3> in (Production Method B).

The compounds of Formula (II)-1f and Formula (III)-1f above are includedin the compound of Formula (I)-1f in (Production Method U) and can beproduced by a similar production method, and these compounds of Formula(I)-1f are included in the compound of Formula (I).

In Formula (I) above, Formula (I)-1c and Formula (I)-1f include opticalisomers. The isomers can be separated through optical resolution usingchiral column chromatography or asymmetric synthesis by a person skilledin the art based on conventional techniques.

(9) The methods for producing the compound of Formula (I)-1d of thepresent invention will be described below.

<Production Method V>

<When n=1 to 2, R^(2a)=R^(2b)=H, Y=CH═CH—COOR′, and n=2 in Formula(I)-1d above>

<Step 1>

A compound of Formula (H-II) is reacted. In accordance with methodsknown in literatures, for example, the method described in [Journal ofOrganic Chemistry, vol. 50 (13), pp. 2259-2263 (1985)], a compound ofFormula (V-I) can be produced by reacting the compound of Formula (H-II)that is easily obtained from a known compound by the method in <Step 1>in (Production Method H) in the presence of an amine such as ammoniumacetate, an alkyl ammonium, and aqueous ammonia, malonic acid, and thelike in a reaction inert solvent including a polar solvent such asethanol, butanol, and water or in a mixed solvent of them at atemperature from 0° C. to a reflux temperature of the solvent.

<Step 2>

The compound of Formula (V-I) is reacted. In accordance with methodsknown in literatures, for example, the method described in [Synlett,vol. 5, pp. 843-838 (2005)], a compound of Formula (VII) can be producedby reacting the compound of Formula (V-I) with a sulfur agent such as anN-chlorosulfonylcarbamic acid ester in the presence of a base such assodium hydride, sodium hydroxide, triethylamine, and pyridine in areaction inert solvent including an ether solvent such as diethyl etherand tetrahydrofuran, an aromatic hydrocarbon solvent such as toluene andbenzene, and a polar solvent such as methanol, ethanol, andN,N-dimethylformamide or in a mixed solvent of them at a temperaturefrom −78° C. to a reflux temperature of the solvent.

<Step 3>

The protective groups P¹ and P² in the compound of Formula (V-II) aredeprotected. A compound of Formula (V-III) can be produced by reactionin a similar manner to that in <Step 3> in (Production Method B).

<Step 4>

The compound of Formula (V-V) is subjected to ring formation reaction.The compound of Formula (I)-1d can be produced by reaction in a similarmanner to that in

<Step 7> in (Production Method M).

The compounds of Formula (II)-1d and Formula (III)-1d above are includedin the compound of Formula (I)-1d in (Production Method V) and can beproduced by a similar production method, and these compounds of Formula(I)-1d are included in the compound of Formula (I).

Similarly, in the production methods in (Production Method W) or later,the compounds of Formula (II)-1d and Formula (III)-1d above are includedin the compound of Formula (I)-1d and can be produced by a similarproduction method, and these compounds of Formula (I)-1d are included inthe compound of Formula (I).

<Production Method W>

<When n=2 and R^(11a)=H>

<Step 1>

A compound of Formula (G-I) is reacted. A compound of Formula (W-I) canbe produced by reacting the compound of Formula (G-I), which is known inthe art or can be easily produced from a known compound, in a similarmanner to that in <Step 1> in (Production Method V).

<Step 2>

The compound of Formula (G-I) is reacted. A compound of Formula (W-II)can be produced by reaction in a similar manner to that in <Step 4> in(Production Method V).

<Step 3>

<When R^(12c≠)Hydrogen Atom>

The compound of Formula (W-II) is reacted. In accordance with methodsknown in literatures, for example, the method described in [Synlett,vol. 5, pp. 697-699 (2002)], a compound of Formula (W-III) can beproduced by reacting the compound of Formula (W-II) with a compound ofR^(12C)OH in the presence of an organophosphorus compound such astriphenylphosphine and an azo compound such as an azodicarboxylic acidester and azodicarboxylic amide in a reaction inert solvent including ahalogenated solvent such as dichloromethane and chloroform, an ethersolvent such as diethyl ether and tetrahydrofuran, an aromatichydrocarbon solvent such as toluene and benzene, and a polar solventsuch as N,N-dimethylformamide and dimethyl sulfoxide or in a mixedsolvent of them at a temperature from 0° C. to a reflux temperature ofthe solvent.

<Step 4>

<When R^(2a) and/or R^(2b)≠Hydrogen Atom>

The compound of Formula (W-III) is subjected to substitution reaction. Acompound of Formula (W-IV) can be produced by reaction in a similarmanner to that in <Step 6> in (Production Method M).

<Step 5>

The protective groups P² and P³ in the compound of Formula (W-IV) aredeprotected. A compound of Formula (W-V) can be produced by reacting thecompound of Formula (W-IV) in a similar manner to that in <Step 3> in(Production Method B).

<Step 6>

The compound of Formula (W-V) is subjected to ring formation reaction. Acompound of Formula (W-VI) can be produced by reacting the compound ofFormula (W-V) in a similar manner to that in <Step 7> in (ProductionMethod M).

<Step 7>

The compound of Formula (W-VI) is protected with a protective group P⁴.A compound of Formula (W VII) can be produced by reacting the compoundof Formula (W-VI) in a similar manner to that in <Step 2> in (ProductionMethod B).

<Step 8>

The protective group P¹ in the compound of Formula (W-VII) isdeprotected. A compound of Formula (W-VIII) can be produced by reactionin a similar manner to that in <Step 3> in (Production Method B).

<Step 9>

The compound of Formula (W-VIII) is subjected to substitution reactionwith a compound of Formula (B-V). A compound of Formula (W-IX) can beproduced by reaction in a similar manner to that in <Step 4> in(Production Method B).

<Step 10>

The protective group P⁴ in the compound of Formula (W-IX) isdeprotected. The compound of Formula (I)-1d can be produced by reactionin a similar manner to that in <Step 3> in (Production Method B).

(9-1) The compound of Formula (I)-1d or Formula (I)-1e can also beproduced by the method below.

<Production Method X>

<When J₁=J_(1a)=CR^(11a), J₂=NR^(12c), and h=1 to 3 in Formula (I)above, that is, in the case of Formula (I)-1d or Formula (I)-1e and whenn=2 and R^(11a)=H>

<Step 1>

A compound of Formula (X-I) is protected with a protective group P². Acompound of Formula (X-II) can be produced by reacting the compound ofFormula (X-I) that is obtained in (Production Method Y) or (ProductionMethod Z) described later in a similar manner to that in <Step 2> in(Production Method B).

<Step 2>

The compound of Formula (X-II) is reacted. A compound of Formula (X-IV)can be produced from the compound of Formula (X-II) and a compound ofFormula (X-III) in accordance with, for example, the method described in[Synlett, vol. 6, pp. 833-836 (2006)].

<Step 3>

<When R^(12c)≠Hydrogen Atom>

The compound of Formula (X-IV) is reacted. A compound of Formula (X-V)can be produced by reaction in a similar manner to that in <Step 3> in(Production Method W).

<Step 4>

The compound of Formula (X-V) is subjected to substitution reaction. Acompound of Formula (X-VI) can be produced by reaction in a similarmanner to that in <Step 2> in (Production Method U).

<Step 5>

The compound of Formula (X-VI) is subjected to substitution reaction. Acompound of Formula (X-VII) can be produced from the compound of Formula(X-VI) in accordance with, for example, the method described in [Journalof the American Chemical Society, vol. 73, pp. 3987-3993 (1953)].

<Step 6>

The protective groups P³ and P⁴ in the compound of Formula (X-VII) aredeprotected. A compound of Formula (X-VIII) can be produced by reactingthe compound of Formula (X-VII) in a similar manner to that in <Step 3>in (Production Method B).

<Step 7>

The compound of Formula (X-VIII) is subjected to ring formationreaction. A compound of Formula (X-IX) can be produced by reacting thecompound of Formula (X-VIII) in a similar manner to that in <Step 7> in(Production Method M).

<Step 8>

The compound of Formula (X-IX) is protected with a protective group P⁵.A compound of Formula(X-X) can be produced by reacting the compound ofFormula (X-IX) in a similar manner to that in <Step 2> in (ProductionMethod B).

<Step 9>

The protective group P¹ in the compound of Formula (X-X) is deprotected.A compound of Formula (X-XI) can be produced by reaction in a similarmanner to that in <Step 3> in (Production Method B).

<Step 10>

The compound of Formula (X-XI) is subjected to substitution reactionwith a compound of Formula (B-V). A compound of Formula (X-XII) can beproduced by reaction in a similar manner to that in <Step 4> in(Production Method B).

<Step 11>

The protective group P⁵ in the compound of Formula (X-XII) isdeprotected. The compound of Formula (I)-1d (when h2=0) or Formula(I)-1e (when h2=1 or 2) can be produced by reaction in a similar mannerto that in <Step 3> in (Production Method B).

The compounds of Formula (II)-1e and Formula (III)-1e above are includedin the compound of Formula (I)-1e in (Production Method X) and can beproduced by a similar production method, and these compounds of Formula(I)-1e are included in the compound of Formula (I).

(9-2) Next, methods for producing the compound of Formula (X-I) will bedescribed.

<Production Method Y>

<When h2=0 and Y=halogen atom in Formula (X-I) above>

<Step 1>

A compound of Formula (Y-I) is reacted. In accordance with methods knownin literatures, for example, the method described in [Tetrahedron, vol.57 (24), pp. 5243-5253 (2001)], a compound of Formula (Y-II) can beproduced by reacting the compound of Formula (Y-I) in the presence of abase such as n-butyllithium and dimethylformamide in a reaction inertsolvent including an ether solvent such as diethyl ether andtetrahydrofuran and an aromatic hydrocarbon solvent such as hexane,toluene, and benzene or in a mixed solvent of them at a temperature from0° C. to a reflux temperature of the solvent.

<Step 2>

The compound of Formula (Y-II) is subjected to reduction. The compoundof Formula (X-I)a can be produced by reacting the compound of Formula(Y-II) in a similar manner to that in <Step 2> in (Production MethodJ-1).

<Production Method Y-1>

<When h2=1 to 2 in Formula (X-I) above>

A compound of Formula (Y1-I) is subjected to reduction. The compound ofFormula (X-I)b can be produced by reacting the compound of Formula (Y-I)in a similar manner to that in <Step 2> in (Production Method J-1).

(9-3) The compound of Formula (V-II) can also be produced by the methodbelow.

<Production Method Z>

<Y=—CH═CH—COOR′ in Formula>

<Step 1>

A compound of Formula (Z-I) can be produced by using a compound ofFormula (G-I), which is known in the art or can be easily produced froma known compound, by the method in <Step 1> and <Step 2> or <Step 3> in(Production Method V).

<Step 2>

The protective group P¹ in the compound of Formula (Z-I) is deprotected.A compound of Formula (Z-II) can be produced by reaction in a similarmanner to that in <Step 3> in (Production Method B).

<Step 3>

The compound of Formula (Z-II) is subjected to substitution reactionwith a compound of Formula (B-V). The compound of Formula (V-II) can beproduced by reaction in a similar manner to that in <Step 4> in(Production Method B).

In Formula (I) above, Formulae (1)-1b, (I)-1c, (I)-1d, (I)-1e, and(I)-1f include optical isomers. The isomers can be separated throughoptical resolution using chiral column chromatography, preferentialcrystallization using an optically active salt, or asymmetric synthesisby a person skilled in the art based on conventional techniques.

<Production Method AA>

<When n=1, 2>

<Step 1>

A compound of Formula (AA-II) can be produced in a similar manner tothat in <Step 2> in (Production Method B) by reacting a compound ofFormula (AA-I), which is known in the art or can be easily produced froma known compound (for example, a phenylacetic acid derivative such as4-hydroxy-a-methylphenylacetic acid (manufactured by Tokyo ChemicalIndustry Co., Ltd.) when the ring B is a benzene ring, or2,3-dihydro-6-hydroxy-3-benzofuran acetic acid,3,4-dihydro-7-hydroxy-2H-1-benzopyran-4-acetic acid,2,3-dihydro-6-hydroxy-benzo[b]thiophene-3-acetic acid, and the like thatcan be produced in accordance with, for example, the method described inWO 2006/083781 pamphlet when the ring B is a bicyclic hetero ring suchas a 2,3-dihydrobenzofuran ring, a 3,4-dihydro-2H-1-benzopyran ring, anda 2,3-dihydrobenzo[b]thiophene ring).

<Step 2>

The compound of Formula (AA-II) is subjected to substitution reaction. Acompound of Formula (AA-IV) can be produced by reacting the compound ofFormula (AA-II) with a compound of Formula (AA-III) in a similar mannerto that in <Step 5> in

(Production Method X).

<Step 3>

The protective group P¹ in the compound of Formula (AA-IV) isdeprotected. A compound of Formula (AA-V) can be produced by reactingthe compound of Formula (A-IV) in a similar manner to that in <Step 3>in (Production Method B).

<Step 4>

The compound of Formula (AA-V) is subjected to ring formation reaction.A compound of Formula (I)-2a/Formula (I)-2c/Formula (I)-2f can beproduced by reacting the compound of Formula (AA-V) in a similar mannerto that in <Step 7> in (Production Method M).

<Production Method BB>

<When n=2>

<Step 1>

A compound of Formula (BB-II) can be produced by reacting a compound ofFormula (BB-I), which is known in the art or can be easily produced froma known compound (for example, a benzyl bromide derivative such as4-(1-bromoethyl)-phenol when the ring B is a benzene ring, and3-(bromomethyl)-6-hydroxy-2,3-dihydrobenzofuran that can be derived from6-hydroxy-3 (2H)-benzofuran in accordance with a method known in aliterature when the ring B is a bicyclic compound such as2,3-dihydro-6-hydroxy-3-benzofuran ring), with a sulfur source such assodium sulfite and potassium sulfite in a similar manner to that in<Step 3> in (Production Method U) (M is a metal such as Na and K inFormula (BB-II)).

<Step 2>

The compound of Formula (BB-II) is subjected to halogenation andsulfonylation, followed by sulfonamidation. A compound of Formula(BB-III) can be produced by reacting the compound of Formula (BB-II) ina similar manner to that in <Step 5> in (Production Method M).

<Step 3>

The compound of Formula (BB-III) is subjected to substitution reaction.A compound of Formula (BB-V) can be produced by reacting the compound ofFormula (BB-III) with a compound of Formula (BB-IV) in a similar mannerto that in <Step 5> in (Production Method X).

<Step 4>

The protective group P¹ in the compound of Formula (BB-V) isdeprotected. A compound of Formula (BB-VI) can be produced by reactingthe compound of Formula (BB-V) in a similar manner to that in <Step 3>in (Production Method B).

<Step 5>

The compound of Formula (BB-VI) is subjected to ring formation reaction.A compound of Formula (I)-3c/Formula (I)-3f can be produced by reactingthe compound of Formula (BB-VI) in a similar manner to that in <Step 7>in (Production Method M).

[Concomitant Drug Containing Compound of the Present Invention]

The compound and pharmaceutical composition of the present invention canbe used in combination with other drugs or medicines by a general methodperformed in medical practice. Particularly, such combination is usedfor the prevention, progress delay, and therapies of the mediating stateof the GPR40 agonist, and is further particularly used against at leastone disease selected from the group consisting of diabetes (Type 1diabetes, Type 2 diabetes, and boederline type diabetes (impairedglucose tolerance (IGT) and/or impaired fasting glycemia (IFG))),insulin resistance, hyperinsulinemia, obesity, adiposity, and variousdiseases derived from or related to these diseases.

Examples of an insulin sensitizer and an anti-diabetic drug include 1)PPAR gamma agonists (specifically, pioglitazone, rosiglitazone,troglitazone, ciglitazone, darglitazone, englitazone, netoglitazone,etc.), 2) biguanide agents (specifically, metformin, buformin,phenformin, etc.), 3) sulfonylureas (specifically, tolbutamide,acetohexamide, chlorpropamide, glibenclamide, gliclazide, glipizide,glimepiride, glipentide, gliquidone, glisolamide, tolazamide, etc.), 4)rapid-acting insulin secretagogues (specifically, nateglinide,mitiglinide, repaglinide, etc.), 5) alpha-glucosidase inhibitors(specifically, acarbose, voglibose, miglitol, camiglibose, adiposin,emiglitate, pradimicin Q, salbostatin, etc.), 6) insulin or insulinderivatives (specifically, insulin zinc suspensions, insulin lispro,insulin aspart, regular insulin, NPH insulin, insulin glargine, insulindetemir, mixed insulin, etc.), 7) GLP-1 and GLP-1 agonists(specifically, exenatide, liraglutide, etc.), 8) DPP-IV inhibitors(specifically, sitagliptin, vildagliptin, alogliptin, saxagliptin,NVP-DPP-728, etc.), and 9) alpha-2 antagonists (specifically,midaglizole, isaglidole, deriglidole, idazoxan, efaroxan, etc.).

Examples of the insulin sensitizer and the anti-diabetic drug alsoinclude a hypolipidemic agent and a dyslipidemia therapeutic agent.Examples of the hypolipidemic agent and the dyslipidemia therapeuticagent include 1) omega-3 fatty acids (specifically, ethyl icosapentate(EPA-E preparation), docosahexaenoic acid (DHA), etc.), 2) HMG-CoAreductase inhibitors (specifically, atorvastatin, simvastatin,pitavastatin, itavastatin, fluvastatin, lovastatin, pravastatin,rivastatin, rosuvastatin, etc.), 3) HMG-CoA synthase inhibitors, 4)cholesterol absorption inhibitors (specifically, ezetimibe), 5)acyl-CoA-cholesterol acyltransferase (ACAT) inhibitors, 6) CETPinhibitors, 7) squalene synthase inhibitors, 8) antioxidants(specifically, probucol, etc.), 9) PPAR alpha agonists (specifically,clofibrate, etofibrate, fenofibrate, bezafibrate, ciprofibrate,gemfibrozil, KRP-101, etc.), 10) PPAR delta agonists, 11) LXR agonists,12) FXR agonists (specifically, INT-747, etc.), 13) MTTP inhibitors, 14)squalene epoxidase inhibitors, and 15) bile acid absorption inhibitors(specifically, cholestyramine, colestipol, etc).

In addition, examples of the insulin sensitizer and the anti-diabeticdrug also include an anti-obesity agent. Specific examples of theanti-obesity agent include 1) CB-1 receptor antagonists (specifically,rimonabant, SR-147778, BAY-65-2520, etc.), 2) monoamine reuptakeinhibitors (specifically, sibutramine, mazindol, etc.), 3) serotoninreuptake inhibitors (specifically, fluoxetine, paroxetine, etc.), 4)lipase inhibitors (specifically, orlistat, cetilistat, etc.), 5)neuropeptide Y (NPY) receptor antagonists (specifically, S-2367, etc.),6) peptide YY (PYY) receptor antagonists, and 7) adrenergic beta-3receptor agonists (specifically, KRP-204, TRK-380/TAC-301, etc).

The therapies can be performed in combination with not only other drugs,but also other therapies. Examples of the therapies include theimprovement of lifestyle through weight control, exercise therapy, anddiet therapy, and radiotherapy.

Against GPR40-involving diseases except for diabetes and obesity, thetherapies can be performed in combination with drugs used in therespective fields.

The combined use of the concomitant drug and conventional drugs againstthe diseases described above enables the dosage of the conventionaldrugs to be reduced, which can reduce the side effects of theconventional drugs. It is needless to say the combining method using thedrugs is not limited to the diseases, and the drugs to be used incombination are not limited to the compounds exemplified above.

To use the compound of the present invention in combination with thedrug to be used in combination, they may be individual preparations orbe a drug combination. In the form of individual preparations, thecompound and the drug can be taken at the same time or can beadministered at different times.

[Producing preparations of prophylactic or therapeutic agents of thepresent invention]

The medicines of the present invention are administered in the form ofpharmaceutical compositions.

The pharmaceutical compositions of the present invention may include atleast the compound of Formula (I) or Formula (II) of the presentinvention and are produced in combination with pharmaceuticallyacceptable additives. More in detail, various dosage forms can beprepared by appropriately combining the compound of the presentinvention and, for example, excipients (for example, lactose, white softsugar, mannitol, microcrystalline cellulose, silicic acid, corn starch,and potato starch), bonding agents (for example, celluloses(hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC),microcrystalline cellulose, saccharide (lactose, mannitol, white softsugar, sorbitol, erythritol, and xylitol), starches (corn starch andpotato starch), gelatinized starch, dextrin, polyvinylpyrrolidone (PVP),macrogol, polyvinyl alcohol (PVA)), lubricants (for example, magnesiumstearate, calcium stearate, talc, and carboxymethylcellulose),disintegrants (for example, starches (corn starch and potato starch),sodium carboxymethyl starch, carmellose, carmellose calcium,croscarmellose sodium, and crospovidone), coating agents (for example,celluloses (hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose(HPMC), aminoalkylmethacrylate copolymers E, and methacrylic copolymersLD), plasticizers (for example, triethyl citrate and macrogol), maskingagents (for example, titanium oxide), colorants, flavoring agents,antiseptics (for example, benzalkonium chloride and p-hydroxybenzoateesters), tonicity agents (for example, glycerin, sodium chloride,calcium chloride, mannitol, and dextrose), pH regulators (for example,sodium hydroxide, potassium hydroxide, sodium carbonate, hydrochloricacid, sulfuric acid, and buffer solutions such as phosphate buffersolutions), stabilizing agents (for example, sugar, sugar alcohol, andxanthan gum), dispersants, antioxidants (for example, ascorbic acid,butylated hydroxyanisole (BHA), propyl gallate, anddl-alpha-tocopherol), buffer agents, preservatives (for example,paraben, benzyl alcohol, and benzalkonium chloride), perfumes (forexample, vanillin, l-menthol, and rose oil), solubilizing agents (forexample, polyoxyethylene hydrogenated castor oil, polysorbate 80,polyethylene glycol, phospholipid cholesterol, and triethanolamine),absorbefacients (for example, sodium glycolate, sodium edetate, sodiumcaprate, acylcarnitines, and limonene), gelators, suspending agents,emulsifiers, and generally used suitable additives and solvents.

Examples of the various dosage forms include tablets, capsules,granules, powderes, pills, aerosols, inhalants, ointments, adhesivepatches, suppositories, injections, troches, liquids, spirits,suspensions, extracts, and elixirs. The dosage forms can be administeredto patients through oral administration, subcutaneous injection,intramuscular injection, intranasal administration, transdermaladministration, intravenous injection, intraarterial injection,perineural administration, epidural administration, administration insubdural cavity, intraventricular administration, rectal administration,inhalation, or the like.

The dosage of the compound of the present invention is generally, 0.005mg to 3.0 g, preferably, 0.05 mg to 2.5 g, and more preferably, 0.1 mgto 1.5 g per day for adults, but can be reduced or increased as neededdepending on symptoms or administration routes.

The compound can be administered as a whole at once or be separatelyadministered by being divided into two to six doses through oraladministration or parenteral administration, or can be administeredthrough repeated administration such as intravenous infusion.

The present specification incorporates, as references, the wholepublications cited in the present specification, for example,related-art documents, publications of unexamined applications, patentpublications, and other patent documents.

PHARMACOLOGICAL TEST EXAMPLES

The present invention is specifically described below with reference totest examples but is not limited to them.

The following pharmacological test examples 1 to 7 provide methods forinvestigating the efficacy of the compound of the present invention.

Pharmacological Test Example 1 Agonist Action on GPR40 of Human Origin

A CHO cell strain stably expressing GPR40 of human origin was used todetermine the agonist action of a title compound. This cell strain wasseeded in a clear bottom 96 well plate at 2×10⁴ cells/100 μL/well. Thecell strain was cultured in a CO₂ incubator overnight using a Ham's F-12medium containing a 10% fetal bovine serum, 100 U/mL penicillin, 0.1mg/mL streptomycin, and 400 μg/mL. Geneticin. Calcium 4 Assay Kit(Molecular Devices) was used as a fluorescent calcium indicator. One mLof 77 mg/mL probenecid (Invitrogen) was added to 100 mL of a calciumindicator solution to prepare a solution (loading solution) mixed with a20 mM HEPES-containing Hanks' balanced salt solution (HBSS) in equalproportions. To the cells from which the culture solution was removed,200 μL of the loading solution was added, and the cells were cultured ina CO₂ incubator for 1 hour. The title compound was diluted with a 20 mMHEPES-containing HBSS and was added to the cells by 50 μL, and thefluctuation of the Ca²+concentration was measured by an intracellularion analyzer. The EC₅₀ value of the title compound was calculated usingthe dose-response curve of fluorescence intensity variation. Table 1indicates the compound of the present invention having an EC₅₀ value ofless than 0.3 μM as A and the compound of the present invention havingan EC₅₀ value of 0.3 μM or more and less than 3 μM as B.

TABLE 1 Compound of EC₅₀ Examples values 1 A 2 A 3 A 4 A 5 A 6 A 7 A 8 A9 A 10 A 11 A 12 A 13 A 14 A 15 B 16 A 17 A 18 B 19 A 20 B 21 A 22 A23(A)-b B 24(A)-a A 25(A)-a A 26 A 27 A 28 B 29 A 30 A 31 A 32 A 33 A 34A 35 A

Pharmacological Test Example 2 Oral Glucose Tolerance Test

A reduction of blood glucose excursion of a subject compound afterglucose load is examined using male C57BL/6J mice or SD rats fastedovernight. The subject compound is suspended with a solvent (forexample, 0.5% carboxymethylcellulose) and is orally administered beforeglucose load. The solvent is singly administered to the control group.Blood specimen collection is performed before compound administration(pre-administration blood collection), after compound administration andimmediately before glucose load, during glucose load, after 15, 30, 60,and 120 minutes, and the blood glucose level of the collected blood ismeasured. The reduction of blood glucose excursion is obtained by orallyadministering a dosage of 0.3 to 10 mg/kg of the preferable compound ofthe compound of the present invention.

Pharmacological Test Example 3 Solubility Test

(1) DMSO precipitation solubility (Kinetic Solubility)

A 10 mM DMSO solution of the compound of the present invention is addedto a 50 mM phosphate buffer solution (pH 7.4) to the final concentrationof 100 μM. The resultant solution is incubated with stirring at 600 rpmfor 1.5 hours at room temperature, and then is filtered through a filterplate (4 μm, MultiScreen Solubility Filter Plate, Millipore). Theabsorbance of the obtained filtrate is measured at the maximumabsorption wavelength using a plate reader (Powerscan HT, (DainipponPharmaceutical)). In this process, DMSO solutions of known concentrationof the test compound (1, 3, 10, 30, and 100 μM) are prepared as standardsolutions for a calibration curve. The absorbance of each of thestandard solutions is measured to generate a calibration curve. Thesolubility (μM) of the compound is calculated using the absorbancevalues of the filtrate and the standard solutions.

(2) Crystal Solubility (Thermodynamic Solubility)

The compound of the present invention is added to water so as to be 1mg/mL

The resultant solution is incubated at 37° C. for 24 hours, and then iscentrifuged. The obtained supernatant is analyzed by HPLC to detect thepeak at the maximum absorption wavelength, and thus, the peak area iscalculated. Similarly, DMSO solutions of known concentration of the testcompound (0.03, 0.1, 0.3, 1, 3, and 10 μg/mL) are added as standardsolutions for a calibration curve. The peak area of each of the standardsolutions is measured. The solubility (μg/mL) of the compound iscalculated using the peak areas of the obtained calibration curve.

Pharmacological Test Example 4 Metabolic Stability Test

The 10 mM DMSO solution of the compound of the present invention isadded to a solution containing liver microsome (human, mouse, or rat;XenoTech) and a NADPH generating systems (water containing beta-NADP,Glucose-6-Phosphate, G-6-PDH(Y), and MgCl₂) to the final concentrationof 1 μM. The resultant solution is incubated at 37° C. for 20 minutes,and then the reaction is terminated by adding acetonitrile. Similarly,samples are collected at predetermined times during the incubation, andthen the reaction is terminated. Each reaction solution is filtrated bycentrifugation using a filter plate (MultiScreen HTS-HV plate,Millipore). The test compound in the filtrate is measured by highperformance liquid chromatogram/mass spectrometry. Similarly, a samplewith a reaction time of 0 is measured as a control. The compoundconcentration of the control is regarded as 100%, and the residual ratioof the compound in each reaction solution is calculated. These residualratios are plotted with respect to the time, and the metabolic clearance(μL/mg/min) is calculated from the slope of the obtained regressionline.

Pharmacological Test Example 5 hERG Inhibition Test By Patch-clamptechnique

An effect against a human ether-a-go-go related gene (hERG) channel ismeasured using a fully automatic patch-clamp system (Patchliner(Nanion)). To confirm the hERG I_(Kr) current of a cell (hERG-HEK(Upstate)), the membrane potential is kept at −80 mV, and a depolarizingpulse is applied to the cell on a regular basis. After the generatedcurrent became stable, a test compound is added. The effect of the testcompound against the hERG channel is confirmed from the change in tailcurrent induced by a repolarizing pulse at −40 mV for 0.5 secondsubsequent to a depolarizing pulse at 40 mV for 0.5 second. Thestimulation is performed at a frequency of once every 10 seconds. Themeasurement is performed at room temperature. The hERG channelinhibition rate is calculated as the reduction rate (suppression rate)of a tail current two minutes after the application of the test compoundrelative to the maximum tail current before the application.

The calculated suppression rate shows the possibility that drug-inducedQT prolongation followed by fatal side effects (such as ventriculartachycardia and sudden death).

Pharmacological Test Example 6 Pharmacokinetics Study (Cassette DosingPK)

The compound of the present invention is orally administrated in asingle dose to T- or 8-week-old male C57BL/6J Jcl mice or SD rats at 1mg/kg (the vehicle is DMSO: Tween 80: ultrapure water=1:1:8 and 10mL/kg). After the administration, the blood of the mouse is collectedfrom the abdominal aorta after 0.25, 0.5, 1, and 2 hours, and the bloodof the rat is collected from the jugular vein after 0.5, 1, 2, and 4hours. The blood is centrifuged (3000 rpm, 15 minutes, and 4° C.) toobtain plasma, and the test compound in the plasma is measured by highperformance liquid chromatogram/mass spectrometry.

Similarly, standard solutions of known concentration of the testcompound (0.01, 0.02, 0.05, 0.1, 0.2, 0.5, and 1 μg/mL) are measured togenerate a calibration curve. The concentration (μg/mL) of the compoundin the plasma is calculated using the calibration curve, and the maximumconcentration in the plasma is indicated by Cmax (μg/mL)

Pharmacological Test Example 7 Safety Assessment Study

The compound of the present invention is orally administrated in asingle dose to mice or rats. No death is confirmed and no noticeablebehavior disorder is observed, and therefore the safety of the compoundof the present invention is shown.

As a result, the compound of the present invention showed an excellentGPR40 agonist action and reduced blood glucose excursion in the singleoral dose glucose tolerance test using normal mice or rats. In thesafety assessment study, no abnormality to indicates low toxicity of thecompound of the present invention.

By performing the tests described above, the compound of the presentinvention is confirmed to have favorable properties in one regard, suchas solubility, metabolic stability, pharmacokinetics, and the avoidanceof an hERG channel inhibition action.

Accordingly, the compound of the present invention is expected to beused as a GPR40 agonist for insulin secretagogues and prophylacticand/or therapeutic agents against diabetes (particularly, Type 2diabetes or boederline type diabetes), obesity, and adiposity.

PREPARATION EXAMPLE

Hereinafter, Examples of the pharmaceutical compositions of the presentinvention are described.

Preparation Example 1 Tablet

Compound of Example 2 100 g Lactose 137 g Crystalline cellulose  30 gHydroxypropylcellulose  15 g Sodium carboxymethyl starch  15 g Magnesiumstearate  3 g

The above components are weighed and then are uniformly mixed. Themixture is formed into tablets having a weight of 150 mg.

Preparation Example 2 Film Coating

Hydroxypropylmethylcellulose 9 g Macrogol 6000 1 g Titanium oxide 2 g

The above components are weighed. Subsequently,hydroxypropylmethylcellulose and macrogol 6000 are dissolved into waterto disperse titanium oxide. The resultant liquid is film-coated on 300 gof the tablets of Preparation Example 1 to obtain film-coated tablets.

Preparation Example 3 Capsules

Compound of Example 6 50 g Lactose 435 g Magnesium stearate 15 g

The above components are weighed and then are uniformly mixed. Adequatehard capsules are each filled with 300 mg of the mixture by weight witha capsule inserter to produce capsules.

Preparation Example 4 Capsules

Compound of Example 8 100 g Lactose 63 g Corn starch 25 gHydroxypropylcellulose 10 g Talc 2 g

The above components are weighed, and then the compound of Example 8,lactose, and corn starch are uniformly mixed. A hydroxypropylcelluloseaqueous solution is added to the resultant mixture to produce granulesby wet granulation. Talc is uniformly mixed with the granules, andadequate hard capsules are each filled with 200 mg of the mixture byweight to produce capsules.

Preparation Example 5 Powders

Compound of Example 11 200 g Lactose 790 g Magnesium stearate 10 g

The above components are weighed and then are uniformly mixed to produce20% powdered drugs.

Preparation Example 6 Granules and Fine Granules

Compound of Example 13 100 g Lactose 200 g Crystalline cellulose 100 gPartially gelatinized starch 50 g Hydroxypropylcellulose 50 g

The above components are weighed, and the compound of Example 13,lactose, crystalline cellulose, and partially pregelatinized starch areuniformly mixed. A hydroxypropylcellulose (HPC) aqueous solution isadded to the resultant mixture to produce granules or fine granules bywet granulation. The granules or fine granules are dried to beformulation of granules or fine granules.

EXAMPLES

Next, in order to describe the present invention further in detail,there are described Examples which should not be construed as limitingthe scope of the present invention.

For the measurement of the nuclear magnetic resonance spectrum (NMR),JEOL JNM-ECX400 FT-NMR (manufactured by JEOL Ltd.) and JEOL JNM-ECX300FT-NMR (manufactured by JEOL Ltd.) were used. As the LC-MS, a WatersFraction Lynx MS system (manufactured by Waters Corporation) was usedand as the column, a Sun Fire column (4.6 mm×5 cm, 5 μm) (manufacturedby Waters Corporation) was used. As a mobile phase, methanol:0.05%acetic acid aqueous solution=1:9 (0 min) to 10:0 (5 min) to 10:0 (7 min)(gradient condition) or methanol:0.05% trifluoroacetic acid aqueoussolution=1:9 (0 min) to 10:0 (5 min) to 10:0 (7 min) (gradientcondition) was used. For the preparative isolation system, gradientconditions appropriately changed depending on the type of the compoundwere used. In the present invention, in the preparative chromatographyof a mixture of optical isomers, an enantiomer having a shorter elutiontime is expressed as A and an enantiomer having a longer elution time isexpressed as B as well as a diastereomer having a shorter elution timeis expressed as a and a diastereomer having a longer elution time isexpressed as b.

Reference Example 1 Synthesis of 4-Hydroxyphenylboronic AcidN-Methyliminodiacetic Acid Ester

A suspension of 4-hydroxyphenylboronic acid (10.3 g) andN-methyliminodiacetic acid (11.0 g) in dimethyl sulfoxide (37 mL)-toluene (333 mL) was heated and refluxed for 1.5 hours. From theresultant reaction mixture, toluene was removed by evaporation underreduced pressure and the reaction mixture was poured into water (400mL). The resultant reaction mixture was stirred for 1.5 hours. Theprecipitate was filtered, washed with water, and then dried underreduced pressure to give the title compound (16.4 g) as a gray whitesolid.

Reference Example 2 Synthesis of3′-(Bromomethyl)-2,6-Dimethyl-4-(3-(Methylsulfonyl)Propoxy)-1,1′-Biphenyl

Concentrated sulfuric acid (1.4 g) was added dropwise to 48% hydrobromicacid (15 ml) at room temperature and[2′,6′-dimethyl-4′-[3-(methylsulfonyl)propoxy]-[1,1′-biphenyl]-3-yl]methanol(25 g) synthesized in accordance with the method described in [WO2008/001931 pamphlet] was divided into five portions and added to themixture. The reaction mixture was stirred at 60° C. for 2.5 hours and48% hydrobromic acid (3.3 ml) was added to the mixture. The mixture wasfurther stirred for 1 hour at the same temperature. After the reactionmixture was allowed to cool, water was added to the reaction mixture.The mixture was extracted with ethyl acetate. The obtained organic phasewas washed with water, then washed with brine, and dried over anhydroussodium sulfate. From the organic phase, the solvent was removed byevaporation under reduced pressure to give the title compound (27 g) asa pale yellow solid.

Example 1 Synthesis of5-[4-[[3-[4-(2-ethoxyethoxy)-2,6-dimethylphenyl]phenyl]methoxy]phenyl]-1-oxo-1,2-thiazolidin-3-one<Step 1> Synthesis of 1-bromo-2,6-dimethyl-4-(2-ethoxyethoxy)benzene

In accordance with the method described in [WO 2005/063729 pamphlet,Reference Example 31], the title compound (12.8 g) was obtained as acolorless oil from 4-bromo-3,5-dimethylphenol (10.0 g) and 2-chloroethylethyl ether (5.94 mL).

<Step 2> Synthesis of(3-(2,6-dimethyl-4-(2-ethoxyethoxy)phenyl)phenyl)methanol

To a mixed solution of the compound (6.40 g) obtained in (Example1)<Step 1> and 3-(hydroxymethyl)phenylboronic acid (3.56 g) in1,4-dioxane (70 mL)- water (7 mL), bis(dibenzylideneacetone)palladium(1.35 g), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (SPhos: 1.92g), and potassium phosphate monohydrate (10.8 g) were sequentially addedand the resultant reaction mixture was heated and stirred at 100° C. for4 hours. To the reaction mixture, water was added and the mixture wasextracted with ethyl acetate. The organic phase was washed with brineand then dried over anhydrous sodium sulfate. From the organic phase,the solvent was removed by evaporation under reduced pressure. Theresultant residue was purified by silica gel column chromatography(eluent; n-hexane:ethyl acetate=80:20 to 75:25) to give the titlecompound (4.13 g) as a colorless oil.

<Step 3> Synthesis of4-((3-(2,6-dimethyl-4-(2-ethoxyethoxy)phenyl)phenypmethoxy)phenylboronicacid N-methyliminodiacetic acid ester

To a solution of the compound (1.50 g) obtained in (Example 1)<Step 2>,the compound (1.49 g) obtained in (Reference Example 1), andtri-n-butylphosphine (1.48 mL) in tetrahydrofuran (50 mL),1,1′-azobis(N,N-dimethylformamide) (1.03 g) was added under ice-coolingand the resultant reaction mixture was stirred at room temperature for 2hours. From the reaction mixture, the solvent was removed by evaporationunder reduced pressure and the resultant residue was purified by silicagel column chromatography (eluent; n-hexane:ethyl acetate) to give thetitle compound (2.37 g) as a white amorphous solid.

<Step 4> Synthesis of 5-chloro-isothiazol-3-ol 1-oxide

To a suspension of 5-chloro-isothiazol-3-ol (31.8 g) in dichloromethane(640 mL), m-chloroperbenzoic acid (content 65%) (60.7 g) was added underice-cooling and the resultant reaction mixture was stirred at roomtemperature for 15 hours. The reaction mixture was filtered and then thefiltrate was concentrated under reduced pressure. To the residue,dichloromethane was added and the precipitate was filtered off. Thefiltrate was concentrated under reduced pressure and the resultantresidue was purified by silica gel chromatography (eluent;n-hexane:ethyl acetate=67:33 to 60:40) to give the title compound (26.0g) as a white solid.

<Step 5> Optical resolution of (Rac)-5-chloro-isothiazol-3-ol 1-oxide

Optical resolution of the compound (30.5 g) obtained in (Example 1)<Step4> was conducted by preparative chromatography (column: CHIRALPAK AS-H(5 cm×25 cm) manufactured by Daicel Chemical Industries, Ltd., eluent;carbon dioxide:methanol=86:14 (V/V), flow rate: 200 g/second, detection:UV 238 nm) to give each enantiomer of the title compound.

Primary fraction (14.7 g, white solid, >99% ee, retention time 4.8minutes (enantiomer A: Example 1-5 (A)))

Secondary fraction (14.1 g, white solid, >98% ee, retention time 5 3minutes (enantiomer B: Example 1-5 (B)))

The optical purity and the retention time were determined under thefollowing conditions.

-   Column: CHIRALPAK AD-H (0.46 cm×25 cm) (manufactured by Daicel    Chemical Industries, Ltd.),-   Eluent: methanol:acetic acid=100:0.1 (v/v),-   Flow rate: 1.0 mL/min,-   Detection: UV 282 nm,-   Column temperature: 40° C.

Hereinafter, the compounds and derivatives of them synthesized using theenantiomer A (Example 1-5 (A)) obtained in (Example 1)<Step 5> isexpressed as “name of the compound+(A)” and the compounds andderivatives of them synthesized using the enantiomer B (Example 1-5 (B))obtained in (Example 1)<Step 5> is expressed as “name of thecompound+(B)”.

<Step 6> Synthesis of5-(4-((3-(2,6-dimethyl4-(2-ethoxyethoxy)phenyl)phenyl)methoxy)phenyl)isothiazol-3-ol1-oxide (A)

To a solution of the compound (0.20 g) obtained in (Example 1)<Step 3>in 1,4-dioxane (3 7 mL), a 1M sodium hydroxide aqueous solution (1.1 mL)was added and the resultant reaction mixture was stirred at roomtemperature for 1.5 hours. To the reaction mixture, the enantiomer A(Example 1-5 (A)) (74 mg) obtained in (Example 1)<Step 5>,2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (SPhos: 31 mg), andpalladium acetate (8.4 mg) were sequentially added and the resultantreaction mixture was heated and stirred at 90° C. for 3 hours. To thereaction mixture, a saturated aqueous ammonium chloride solution wasadded and the mixture was extracted with ethyl acetate. The organicphase was washed with brine and then dried over anhydrous sodiumsulfate. From the organic phase, the solvent was removed by evaporationunder reduced pressure and the resultant residue was purified by LC/MSto give the title compound (9.2 mg) as a pale yellow amorphous solid.

<Step 7> Synthesis of5-[4-[[3-[[4-(2-ethoxyethoxy)-2,6-dimethylphenyl]phenyl]methoxy]phenyl]-1-oxo-1,2-thiazolidin-3-one(A)

To a solution of the compound (50 mg) obtained in (Example 1)<Step 6> inabsolute THF (1 mL), a solution of 1M L-Selectride in tetrahydrofuran(0.31 mL) was added at 0° C. and the resultant reaction mixture wasstirred at the same temperature for 1.5 hours. To the reaction mixture,1M hydrochloric acid was added and the mixture was extracted with ethylacetate. The organic phase was washed with brine and then dried overanhydrous sodium sulfate. From the organic phase, the solvent wasremoved by evaporation under reduced pressure and the resultant residuewas purified by silica gel column chromatography (eluent; n-hexane:ethylacetate) to give the title compound (4.6 mg) as a white solid. Theobtained compound by the reduction in this step is a mixture ofdiastereomers having a new asymmetric center.

The compounds of Examples 2 to Example 4 below were synthesized by thesame method or a similar method in Example 1 from each corresponding rawmaterial through a corresponding substituted phenylboronic acid esterand further through a corresponding substituted isothiazole.

Example 25-[4-[[3-[4-(2-ethoxyethoxy)-3-fluoro-2,6-dimethylphenyl]phenyl]methoxy]phenyl]-1-oxo-1,2-thiazolidin-3-one(A) Example 35-[4-[[3-[3-fluoro-4-(3-hydroxy-3-methylbutoxy)-2,6-dimethylphenyl]phenyl]methoxy]phenyl]-1-oxo-1,2-thiazolidin-3-one(A) Example 45-[4-[[3-[4-(3-hydroxy-3-methylbutoxy)-2,6-dimethylphenyl]phenyl]methoxy]phenyl]-1-oxo-1,2-thiazolidin-3-one(A) Example 5 Synthesis of optically active5-[4-[[3-[2,4-dimethyl-6-(3-methylsulfonylpropoxy)pyridin-3-yl]phenyl]methoxy]phenyl]-1-oxo-1,2-thiazolidin-3-one(A)-a and (A)-b <Step 1> Synthesis of5-(4((3-(2,4-dimethyl-6-(3-(methylsulfonyl)propoxy)pyridin-3-yl)phenyl)methoxy)phenyl)isothiazol-3-ol1-oxide (A)

The title compound was synthesized by the same method or a similarmethod in <Step 1> to <Step 6> in (Example 1) from a corresponding rawmaterial through a corresponding substituted phenylboronic acid ester.

<Step 2> Synthesis of5-[4-[[3-[2,4-dimethyl-6-(3-methylsulfonylpropoxy)pyridin-3-yl]phenyl]methoxy]phenyl]-1-oxo-1,2-thiazolidin-3-one(A)-a and (A)-b

To a solution of the compound (200 mg) obtained in (Example 5)<Step 1>in absolute THF (6 mL), a solution of 1M L-Selectride in tetrahydrofuran(1.5 mL) was added at 0° C. and the resultant reaction mixture wasstirred at the same temperature for 1 hour. To the reaction mixture, 1Mhydrochloric acid was added and the mixture was extracted with ethylacetate. The organic phase was washed with brine and then dried overanhydrous sodium sulfate. From the organic phase, the solvent wasremoved by evaporation under reduced pressure and the resultant residuewas purified by LC/MS to give each diastereomer of the title compound.

Primary fraction (1.6 mg, pale yellow solid, retention time 5.25minutes, diastereomer a: Example 5 (A)-a)

Secondary fraction (3.4 mg, pale yellow solid, retention time 5.32minutes, diastereomer b: Example 5 (A)-b)

Hereinafter, for example, the mixture of diastereomers that are obtainedby the reduction in Example 5<Step 2> using the enantiomer A (Example5-1 (A)) obtained in Example 5 <Step 1> can be separated into opticallyactive diastereomers as shown in Example 5 <Step 2>. For example, when aresolution column is used, the primary fraction that is firstly elutedin the separation condition is expressed as “name of the compound+a” asa diastereomer a (Example 5 (A)-a) and the secondary fraction that iseluted later is expressed as “name of the compound+b” as a diastereomerb (Example 5 (A)-b).

For example, Example 5-1 (B), Example 5 (B)-a, and Example 5 (B)-b cansimilarly be obtained when the enantiomer B obtained in Example 1 <Step5> is used in Example 5 <Step 1>.

The compound of Example 6 below was synthesized by the same method or asimilar method in Example 5 form each corresponding raw material througha corresponding substituted phenylboronic acid ester and further througha corresponding substituted isothiazole.

Example 65-[4-[[3-[6-(3-hydroxy-3-methylbutoxy)-2,4-dimethylpyridin-3-yl]phenyl]methoxy]phenyl]-1-oxo-1,2-thiazolidin-3-one(A)-a trifluoroacetic acid salt and (A)-b trifluoroacetic acid salt

Primary fraction (6.4 mg, colorless amorphous solid, retention time 5.72minutes, diastereomer a: Example 6 (A)-a)

Secondary fraction (8.1 mg, colorless oil, retention time 5.77 minutes,diastereomer b: Example 6 (A)-b)

Example 7 Synthesis of5-[4-[[3-[4-(3-hydroxy-3-methylbutoxy)-2,5-dimethylphenyl]phenyl]methoxy]phenyl]-1-oxo-1,2-thiazolidin-3-one(A)-a and (A)-b <Step 1> Synthesis of3-hydroxy-5-(4-((4′(3-hydroxy-3-methylbutoxy)-2′,5′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)phenyl)isothiazole1-oxide(A)

The title compound was synthesized by the same method or a similarmethod in <Step 1> to <Step 6> in (Example 1) from a corresponding rawmaterial through a corresponding substituted phenylboronic acid ester.

<Step 2> Synthesis of5-[4-[[3-[4-(3-hydroxy-3-methylbutoxy)-2,5-dimethylphenyl]phenyl]methoxy]phenyl]-1-oxo-1,2-thiazolidin-3-one(A)-a and (A)-b

To a solution of the compound (100 mg) obtained in (Example 7)<Step 1>in absolute THF (3 mL), a solution of 1M L-Selectride in tetrahydrofuran(0 79 mL) was added at 0° C. and the resultant reaction mixture wasstirred at the same temperature for 1.5 hours. To the reaction mixture,1M hydrochloric acid was added and the mixture was extracted with ethylacetate. The organic phase was washed with brine and then dried overanhydrous sodium sulfate. From the organic phase, the solvent wasremoved by evaporation under reduced pressure and the resultant residuewas separated and purified by LC/MS. Optical resolution of the resultantsolid was conducted by preparative chromatography (column: CHIRALPAK IB(2 cm×25 cm) manufactured by Daicel Chemical Industries, Ltd., eluent;hexane:ethanol:trifluoroacetic acid=70:30:0.1 (V/V), flow rate: 17mL/min) to give each diastereomer of the title compound. The retentiontimes were determined by LC/MS.

Primary fraction (10 mg, colorless amorphous solid, retention time 6.20minutes, diastereomer a: Example 7 (A)-a)

Secondary fraction (21 mg, colorless amorphous solid, retention time6.10 minutes, diastereomer b: Example 7 (A)-b)

Example 8 Synthesis of5-[4-[[3-[4-(3-hydroxypropoxy)-2,6-dimethylphenyl]phenyl]methoxy]phenyl]-1-oxo-1,2-thiazolidin-3-one(A)< <Step 1> Synthesis of1-bromo-4-(3-((tert-butyldimethylsilyl)oxy)propoxy)-2,6-dimethylbenzene

In accordance with the method in (Example 1)<Step 1>, the title compound(7.60 g) was obtained as a colorless oil from 4-bromo-3,5-dimethylphenol(4.00 g) and 3-((tert-butyldimethylsilyl)oxy)propyl bromide (5.55 g).

<Step 2> Synthesis of(3-(2,6-dimethyl-4-(3-(tert-butyldimethylsilypoxy)propoxyphenyl)phenyl)methanol

In accordance with the method in (Example 1)<Step 2>, the title compound(1.34 g) was obtained as a brown oil from the compound (3.60 g) obtainedin (Example 8)<Step 1>.

<Step 3> Synthesis of4-((3-(4-(3-((tert-butyldimethylsilypoxy)propoxy)-2,6-dimethylphenyl)phenyl)methoxy)phenylboronic acid N-methyliminodiacetic acid ester

In accordance with the method in (Example 1)<Step 3>, the title compound(1.21 g) was obtained as a pale yellow amorphous solid from the compound(1.20 g) obtained in (Example 8)<Step 2>.

<Step 4> Synthesis of5-(4-((3-(2,6-dimethyl-4-(3-hydroxypropoxy)phenyl)phenyl)methoxy)phenyl)isothiazol-3-ol1-oxide (A)

To a solution of the compound (0.20 g) obtained in (Example 8)<Step 3>in 1,4-dioxane (3 2 mL), a 1M sodium hydroxide aqueous solution (0.9 mL)was added and the resultant reaction mixture was stirred at roomtemperature for 1.5 hours. To the reaction mixture, the enantiomer A (62mg) obtained in (Example 1)<Step 5>,2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (SPhos: 26 mg), andpalladium acetate (7.1 mg) were sequentially added and the resultantreaction mixture was heated and stirred at 100° C. for 2 hours. To thereaction mixture, a saturated aqueous ammonium chloride solution wasadded and the mixture was extracted with ethyl acetate. The organicphase was washed with brine and then dried over anhydrous sodiumsulfate. From the organic phase, the solvent was removed by evaporationunder reduced pressure and the resultant residue was dissolved inethanol (5.0 mL) and tetrahydrofuran (5.0 mL). To the solution,concentrated hydrochloric acid (4.1 mL) was added and the resultantreaction mixture was stirred at room temperature for 8 hours. To thereaction mixture, a saturated aqueous sodium hydrogen carbonate wasadded to make the mixture weak acidic and the mixture was extracted withethyl acetate. The organic phase was washed with brine and then driedover anhydrous sodium sulfate. From the organic phase, the solvent wasremoved by evaporation under reduced pressure and the resultant residuewas purified by LC/MS to give the title compound (23 mg) as a paleyellow amorphous solid.

<Step 5> Synthesis of5-[4-[[3-[4-(3-hydroxypropoxy)-2,6-dimethylphenyl]phenyl]methoxy]phenyl]-1-oxo-1,2-thiazolidin-3-one(A)

In accordance with the method in (Example 1)<Step 7>, the title compound(4.2 mg) was obtained as a pale yellow amorphous solid from the compound(11 mg) obtained in (Example 8)<Step 4>. The title compound is a mixtureof diastereomers.

The compounds of Example 9 to Example 10 below were synthesized by thesame method or a similar method in Example 8 form each corresponding rawmaterial through a corresponding substituted phenylboronic acid esterand further through a corresponding substituted isothiazole.

Example 95-[4-[[3-[4-[(2R)-2,3-dihydroxypropoxy]-2,6-dimethylphenyl]phenyl]methoxy]phenyl]-1-oxo-1,2-thiazolidin-3-one(A) Example 105-[4-[[3-[4-[3-hydroxy-2-(hydroxymethyl)propoxy]-2,6-dimethylphenyl]phenyl]methoxy]phenyl]-1-oxo-1,2-thiazolidin-3-one (A) Example 11 Synthesis of5-[4-[[3-[4-(3-aminopropoxy)-2,6-dimethylphenyl]phenyl]methoxy]phenyl]-1-oxo-1,2-thiazolidin-3-onetrifluoroacetic acid salt <Step 1> Synthesis of3-(4-bromo-3,5-dimethylphenoxy)propyl)carbamic acid tert-butyl ester

In accordance with the method in (Example 1)<Step 3>, the title compound(6.6 g) was obtained as a white solid from 4-bromo-3,5-dimethylphenol(5.00 g) and (3-hydroxypropyl)carbamic acid tert-butyl ester (5.2 g).

<Step 2> Synthesis of(3-((3′-formyl-2,6-dimethyl-[1,1′-biphenyl]-4-yl)oxy)propyl)carbamicacid tert-butyl ester

In accordance with the method in (Example 1)<Step 2>, the title compound(1.95 g) was obtained as a red oil from the compound (2.3 g) obtained in(Example 11)<Step 1> and 3-formylphenylboronic acid (0.95 g).

<Step 3> Synthesis of3-((3′-hydroxymethyl-2,6-dimethyl-[1,1′-biphenyl]-4-yl)oxy)propyl)carbamicacid tert-butyl ester

The compound (1.84 g) obtained in (Example 11)<Step 2> was dissolved ina solution of tetrahydrofuran (12.0 mL) and methanol (6.0 mL). To thesolution, sodium borohydride (0.18 g) was gradually added underice-cooling. The reaction mixture was allowed to reach room temperatureand stirred for 2 hours. To the reaction mixture, a saturated aqueousammonium chloride solution was added to make the mixture pH 7 and themixture was extracted with ethyl acetate. The organic phase was washedwith brine and then dried over anhydrous sodium sulfate. From theorganic phase, the solvent was removed by evaporation under reducedpressure and the resultant residue was purified by silica gel columnchromatography (eluent; n-hexane:ethyl acetate=75:25 to 70:30) to givethe title compound (1.73 g) as an amorphous solid.

<Step 4> Synthesis of(3-((2,6-dimethyl-3′-(4-(6-methyl-4,8-dioxo-1,3,6,2-dioxazaborocan-2-yl)phenoxy)methyl-[1,1′-biphenyl]-4-yl)oxy)propyl)carbamicacid tert-butyl ester

In accordance with the method in Example 1 <Step 3>, the title compound(2.09 g) was obtained as a white amorphous solid from the compound (1.70g) obtained in (Example 11)<Step 3>.

<Step 5> Synthesis of (3-((2,6-dimethyl-3′-((4(4-(1-oxide-3-oxo-2,3-dihydroisothiazol-5-yl)phenoxy)methyl-[1,1′-biphenyl]-4-yl)oxy)propyl)carbamicacid tert-butyl ester (A)

In accordance with the method in Example 1 <Step 6>, the title compound(45.6 mg) was obtained as a white amorphous solid from the compound (100mg) obtained in (Example 11)<Step 4> using the enantiomer A (Example 1-5(A)) obtained in (Example 1)<Step 5>.

<Step 6> Synthesis of5-(4-((4′-(3-aminopropoxy)-2′,6′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)phenyl)isothiazol-3(2H)-one1-oxide (A)

The compound (45 mg) obtained in (Example 11)<Step 5> was dissolved inethyl acetate (1.0 mL). To the solution, a solution of 4M hydrogenchloride in ethyl acetate (1.0 mL) was added and the resultant reactionmixture was stirred at room temperature over night. The reaction mixturewas concentrated under reduced pressure and dried to give the titlecompound (49 mg) as a yellow solid.

<Step 7> Synthesis of5-[4-[[3-[4-[(3R)-3-hydroxybutoxy]-2,6-dimethylphenyl]phenyl]methoxy]phenyl]-1-oxo-1,2-thiazolidin-3-one(A)

In accordance with the method in (Example 1)<Step 7>, the title compound(26 mg) was obtained as a colorless amorphous solid from the compound(50 mg) obtained in (Example 11)<Step 6>. The obtained compound is amixture of diastereomers.

Example 12 Synthesis of5-[4-[[3-[4-[(3R)-3-hydroxybutoxy]-2,6-dimethylphenyl]phenyl]methoxy]phenyl]-1-oxo-1,2-thiazolidin-3-one(A)< <Step 1> Synthesis of (3R)-3-acetoxybutoxy 4-methylbenzenesulfonate

The hydroxy group in (3R)-3-hydroxybutoxy 4-methylbenzenesulfonate (35.0g) that was synthesized in accordance with the method in [Tetrahedron:Asymmetry, vol. 5 (1), pp. 117-118 (1994)] was acetylated in a commonprocedure to give the title compound (15.6 g) as a yellow oil.

<Step 2> Synthesis of4-((3R)-3-acetoxybutoxy)-1-bromo-2,6-dimethylbenzene

In accordance with the method in (Example 1)<Step 1>, the title compound(4.09 g) was obtained as a colorless oil from 4-bromo-3,5-dimethylphenol(5.00 g) and the compound (7.83 g) obtained in (Example 12)<Step 1>.

<Step 3> Synthesis of(3-(4-((3R)-3-acetoxybutoxy)-2,6-dimethylphenyl)phenyl)methanol

In accordance with the method in (Example 1)<Step 2>, the title compound(1.36 g) was obtained as a brown oil from the compound (2.00 g) obtainedin (Example 12)<Step 2>.

<Step 4> Synthesis of4-((3-(4-((3R)-3-acetoxybutoxy)-2,6-dimethylphenyl)phenyl)methoxy)phenylboronicacid N-methyliminodiacetic acid ester

In accordance with the method in (Example 1)<Step 3>, the title compound(1.83 g) was obtained as a white solid from the compound (1.20 g)obtained in (Example 12)<Step 3>.

<Step 5> Synthesis of5-(4-((3-(2,6-dimethyl-4-((3R)-3-hydroxybutoxy)phenyl)phenyl)methoxy)phenyl)isothiazol-3-ol1-oxide (A)

To a solution of the compound (0.40 g) obtained in (Example 12)<Step 4>in 1,4-dioxane (7.0 mL), a 1M sodium hydroxide aqueous solution (2.1 mL)was added and the resultant reaction mixture was stirred at roomtemperature for 1.5 hours. To the reaction mixture, the enantiomer A(137 mg) obtained in (Example 1)<Step 5>,2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (SPhos: 57 mg), andpalladium acetate (39 mg) were sequentially added and the resultantreaction mixture was heated and stirred at 100° C. for 2 hours. To thereaction mixture, a saturated aqueous ammonium chloride solution wasadded and the mixture was extracted with ethyl acetate. The organicphase was washed with brine and then dried over anhydrous sodiumsulfate. From the organic phase, the solvent was removed by evaporationunder reduced pressure and the resultant residue was dissolved inethanol (5.0 mL). To the solution, a 1M sodium hydroxide aqueoussolution (4.9 mL) was added and the resultant reaction mixture wasstirred at room temperature for 8 hours. To the reaction mixture, asaturated aqueous ammonium chloride solution was added to make themixture weak acidic and the mixture was extracted with ethyl acetate.The organic phase was washed with brine and then dried over anhydroussodium sulfate. From the organic phase, the solvent was removed byevaporation under reduced pressure and the resultant residue waspurified by LC/MS to give the title compound (29 mg) as a pale yellowamorphous solid.

<Step 6> Synthesis of5-[4-[[3-[4-[(3R)-3-hydroxybutoxy]-2,6-dimethylphenyl]phenyl]-methoxy]phenyl]-1-oxo-1,2-thiazolidin-3-one(A)

In accordance with the method in (Example 1)<Step 7>, the title compound(5.2 mg) was obtained as a pale yellow amorphous solid from the compound(11 mg) obtained in (Example 12)<Step 5>. The obtained compound is amixture of diastereomers.

Example 13 Synthesis of 5-[4-[[3-[2,6-dimethyl4-(3-methylsulfonylpropoxy)phenyl]phenyl]methoxy]phenyl]-1-oxo-1,2-thiazolidin-3-one(A)< <Step 1> Synthesis of (3-(2,6-dimethyl4-((tert-butyldimethylsilyl)oxy)phenyl)phenyl)methanol

In accordance with the method in (Example 1)<Step 2>, the title compound(10.4 g) was obtained as an orange solid from1-bromo-4-((tert-butyldimethylsilyl)oxy)-2,6-dimethylbenzene (15.0 g)that was synthesized in accordance with the method described in [WO2005/063729 pamphlet].

<Step 2> Synthesis of4-((3-(2,6-dimethyl-4-((tert-butyldimethylsilypoxy)phenyl)phenypmethoxy)phenylboronicacid N-methyliminodiacetic acid ester

In accordance with the method in (Example 1)<Step 3>, the title compound(0.24 g) was obtained as a pale yellow amorphous solid from the compound(0.20 g) obtained in (Example 13)<Step 1>.

<Step 3> Synthesis of4-((3-(2,6-dimethyl-4-hydroxyphenyl)phenyl)methoxy)phenylboronic acidN-methyliminodiacetic acid ester

To a solution of the compound (4.18 g) obtained in (Example 13)<Step 2>in tetrahydrofuran (70 mL), a solution of 1M tetrabutylammonium fluoridein tetrahydrofuran (14.6 mL) was added under ice-cooling and the mixturewas stirred under ice-cooling for 30 minutes. Water was added to thereaction mixture and the mixture was extracted with ethyl acetate. Theorganic phase was washed with brine and then dried over anhydrous sodiumsulfate. From the organic phase, the solvent was removed by evaporationunder reduced pressure and the resultant residue was purified by silicagel column chromatography (eluent; n-hexane:ethyl acetate=33:67 to20:80) to give the title compound (1.06 g) as a beige amorphous solid.

<Step 4> Synthesis of4-((3-(2,6-dimethyl-4-(3-(methylsulfonyl)propoxy)phenyl)phenyl)methoxy)phenylboronicacid N-methyliminodiacetic acid ester

In accordance with the method in (Example 1)<Step 1>, the title compound(79 mg) was obtained as a white solid from the compound (0.20 g)obtained in (Example 13)<Step 3> and 3-(methylsulfonyl)propyl4-methylbenzenesulfonate (0.14 g) synthesized in accordance with themethod described in [WO 2007/018314 pamphlet].

<Step 5> Synthesis of 5-(4-((3-(2,6-dimethyl4-(3-(methylsulfonyl)propoxy)phenyl)phenyl)methoxy)phenyl)isothiazol-3-ol1-oxide (A)

In accordance with the method in (Example 1)<Step 6>, the title compound(15 mg) was obtained as a beige solid from the compound (76 mg) obtainedin (Example 13)<Step 4> using the enantiomer A (Example 1-5 (A))obtained in (Example 1)<Step 5>.

<Step 6> Synthesis of 5-[4-[[3-[2,6-dimethyl4-(3-methylsulfonylpropoxy)phenyl]phenyl]methoxy]phenyl]-1-oxo-1,2-thiazolidin-3-one(A)-a and (A)-b

In accordance with the method in (Example 7)<Step 2>, each diastereomerof the title compound was obtained from the compound (100 mg) obtainedin (Example 13)<Step 5>. The separation condition was as follows.Preparative chromatography (column: CHIRALPAK IB (2 cm×25 cm)manufactured by Daicel Chemical Industries, Ltd., eluent;hexane:ethanol:trifluoroacetic acid=50:50:0.1 (V/V), flow rate: 17mL/min). The retention times were determined by LC/MS.

Primary fraction (7.8 mg, colorless amorphous solid, retention time 5.62minutes, diastereomer a: Example 13 (A)-a)

Secondary fraction (6.0 mg, colorless amorphous solid, retention time5.53 minutes, diastereomer b: Example 13 (A)-b)

Example 14 Synthesis of5-[4-[[3-(2,6-dimethylphenyl)phenyl]methoxy]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one<Step 1> Synthesis of(4-((2′,6′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)phenyl)carbamic acidtert-butyl ester

To a solution of (2′,6′-dimethyl-[1,1′-biphenyl]-3-yl)methanol (4.0 g),4-hydroxycarbamic acid tert-butyl ester (5.91 g), andtri-n-butylphosphine (6.97 mL) in tetrahydrofuran (80 mL),1,1′-azobis(N,N-dimethylformamide) (4.87 g) was added under ice-coolingand the resultant reaction mixture was stirred at room temperature for62 hours. The precipitated solid was filtered off and the solvent in thefiltrate was removed by evaporation under reduced pressure. To theresultant residue, water was added and the mixture was extracted withethyl acetate. The organic phase was washed with brine and then driedover anhydrous sodium sulfate. From the organic phase, the solvent wasremoved by evaporation under reduced pressure and the resultant residuewas purified by silica gel column chromatography (eluent; n-hexane:ethylacetate=95:5) twice to give the title compound (6.17 g) as a colorlessamorphous solid.

<Step 2> Synthesis of4-((2′,6′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)aniline

The compound (6.15 g) obtained in (Example 14)<Step 1> was dissolved inethyl acetate (27 mL). To the solution, a solution of 4M hydrogenchloride in ethyl acetate (19 mL) was added and the resultant reactionmixture was stirred at room temperature over night. The reaction mixturewas diluted with ethyl acetate. To the mixture, a saturated aqueoussodium hydrogen carbonate solution was added to make the mixture basicand the mixture was extracted with ethyl acetate. The obtained organicphase was washed with brine and then dried over anhydrous sodiumsulfate. The organic phase was concentrated under reduced pressure togive the title compound (4.58 g) as a pale brown oil.

<Step 3> Synthesis of tert-butyl2-((4-((2′,6′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)phenyl)amino)acetate

To a solution of the compound (0.50 g) obtained in (Example 14)<Step 2>in N,N′-dimethylformamide (3.3 mL), diisopropylethylamine (0.57 mL) andtert-butyl 2-bromoacetate (0.23 mL) were sequentially added and theresultant reaction mixture was stirred at 60° C. for 4 hours. Thereaction mixture was allowed to reach room temperature, then dilutedwith water, and extracted with ethyl acetate. The obtained organic phasewas washed with brine and then dried over anhydrous sodium sulfate. Fromthe organic phase, the solvent was removed by evaporation under reducedpressure. The resultant residue was purified by silica gel columnchromatography (eluent; n-hexane:ethyl acetate=90:10) to give the titlecompound (0.60 g) as a pale yellow oil.

<Step 4> Synthesis of tert-butyl2((N-(tert-butoxycarbonypsulfamoyl)(4-((2′,6′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)phenyl)amino)acetate

To a solution of tert-butanol (0.14 mL) in methylene chloride (0.70 mL),chlorosulfonyl isocyanate (0.13 mL) was added under ice-cooling. Theresultant reaction mixture was stirred at room temperature for 30minutes to prepare a solution of chlorosulfonyl carbamic acid tert-butylester in methylene chloride. The mixed solution was added to a solutionof the compound (0.30 g) obtained in (Example 14)<Step 3> anddiisopropylethylamine (0.38 mL) in methylene chloride (0.70 mL) underice-cooling and the resultant reaction mixture was stirred at roomtemperature for 4 hours. The reaction solution was diluted with waterand extracted with methylene chloride. The obtained organic phase waswashed with brine and then dried over anhydrous sodium sulfate. From theorganic phase, the solvent was removed by evaporation under reducedpressure to give a mixture (0.48 g) containing the title compound as acolorless amorphous solid.

<Step 5> Synthesis of2-((4-((2′,6′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)phenyl)(sulfamoyl)amino)aceticacid

To a solution of the compound (0.30 g) obtained in (Example 14)<Step 4>in methylene chloride (3.0 mL), trifluoroacetic acid (0.8 mL) was addedunder ice-cooling and the resultant reaction mixture was stirred at roomtemperature for 21 hours. To the reaction solution, water was added andthe mixture was extracted with methylene chloride. The obtained organicphase was washed with brine and then dried over anhydrous sodiumsulfate. From the organic phase, the solvent was removed by evaporationunder reduced pressure to give the title compound (0.20 g) as a brownamorphous solid.

<Step 6> Synthesis of5-[4-[[3-(2,6-dimethylphenyl)phenyl]methoxy]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one

To a solution of the compound (80.0 mg) obtained in (Example 14)<Step 5>in tetrahydrofuran (1.2 mL), 1-hydroxybenzotriazole monohydrate (27.8mg) and 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride(WSC—HCl: 34.8 mg) were sequentially added and the resultant reactionmixture was stirred at room temperature for 10 minutes. Subsequently,triethylamine (27.84 μl) was added and the resultant reaction mixturewas stirred at room temperature for 15 hours. From the reaction mixture,the solvent was removed by evaporation under reduced pressure. To theresidue, ethyl acetate was added. The mixture was sequentially washedwith 1M hydrochloric acid and brine and then dried over anhydrous sodiumsulfate. From the organic phase, the solvent was removed by evaporationunder reduced pressure. The resultant residue was purified bypreparative TLC (eluent; methylene chloride:methanol=20:1, 1% aceticacid). The obtained compound was triturated with ether to give the titlecompound (10.2 mg) as a brown solid.

Example 15 Synthesis of5-[4-[[3-[2,6-dimethyl-4-(3-methylsulfonylpropoxy)phenyl]phenyl]methoxy]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one<Step 1> Synthesis of(4-((2′,6′-dimethyl-4′-(3-methylsulfonyl)propoxy-[1,1′-biphenyl]-3-yl)methoxy)phenyl)carbamicacid tert-butyl ester

In accordance with the method in (Example 14)<Step 1>, the titlecompound (1.54 g) was obtained as a white amorphous solid from{2′,6′-dimethyl-4′-[3-(methylsulfonyl)propoxy]-[1,1′-biphenyl]-3-yl}methanol(1.0 g) that was synthesized in accordance with the method described in[WO 2008/001931 pamphlet].

<Step 2> Synthesis of4((2′,6′-dimethyl-4′-(3-methylsulfonyl)propoxy-[1,1′-biphenyl]-3-yl)methoxy)aniline

In accordance with the method in (Example 14)<Step 2>, the titlecompound (1.18 g) was obtained as a pale yellow oil from the compound(1.53 g) synthesized in (Example 15)<Step 1>.

<Step 3> Synthesis of ethyl2-((4((2′,6′-dimethyl-4′[3-(methylsulfonyl)propoxy]-[1,1′-biphenyl]-3-yl)methoxy)phenyl)amino)acetate

In accordance with the method in (Example 14)<Step 3>, the titlecompound (0.40 g) was obtained as a pale yellow oil from the compound(0.40 g) obtained in (Example 15)<Step 2> and ethyl 2-bromoacetate (95.6μl).

<Step 4> Synthesis of ethyl2((N-(tert-butoxycarbonyl)sulfamoyl)(4-((2′,6′-dimethyl-4′-(3-(methylsulfonyl)propoxy)-[1,1′-biphenyl]-3-yl)methoxy)phenyl)amino)acetate

In accordance with the method in (Example 14)<Step 4>, the titlecompound (0.55 g) was obtained as a brown amorphous solid from thecompound (0.38 g) obtained in (Example 15)<Step 3>.

<Step 5> Synthesis of ethyl2-((4-((2′,6′-dimethyl-4′-[3-(methylsulfonyl)propoxy]-[1,1′-biphenyl]-3-yl)methoxy)phenyl)(sulfamoyl)amino)acetate

In accordance with the method in (Example 14)<Step 5>, the titlecompound (0.47 g) was obtained as a brown amorphous solid from thecompound (0.53 g) obtained in (Example 15)<Step 4>.

<Step 6> Synthesis of5-[4-[[3-[2,6-dimethyl-4-(3-methylsulfonylpropoxy)phenyl]phenyl]methoxy]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one

To a solution of the compound (0.20 g) obtained in (Example 15)<Step 5>in ethanol (0.80 mL), a 2M sodium hydroxide aqueous solution (0.33 mL)was added under ice-cooling and the resultant reaction mixture wasstirred for 30 minutes. To the reaction solution, ethyl acetate and 1Mhydrochloric acid were added and the mixture was extracted with ethylacetate. The organic phase was dried over anhydrous sodium sulfate. Fromthe organic phase, the solvent was removed by evaporation under reducedpressure and the resultant residue was purified by LC/MS to give thetitle compound (17 mg) as a pale beige solid.

Example 16 Synthesis of5-[2-chloro-4-[[3-(2,6-dimethylphenyl)phenyl]methoxy]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one<Step 1> Synthesis of (2-chloro-4-hydroxyphenyl)carbamic acid tert-butylester

To a solution of 4-amino-3-chlorophenol hydrochloride (1.0 g) andtriethylamine (0.77 mL) in tetrahydrofuran (4.6 mL), di-tert-butylcarbonate (1.39 mL) was slowly added dropwise and the resultant reactionmixture was heated and refluxed for 8 hours. The reaction mixture wasallowed to reach room temperature and added to a saturated aqueousammonium chloride. The mixture was extracted with ethyl acetate and theorganic phase was dried over anhydrous sodium sulfate. From the organicphase, the solvent was removed by evaporation under reduced pressure togive a mixture (1.42 g) containing the title compound as a pale brownsolid.

<Step 2> Synthesis of(2-chloro-4-((2′,6′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)phenyl)carbamicacid tert-butyl ester

In accordance with the method in (Example 14)<Step 1>, a mixture (0.83g) containing the title compound was obtained as a colorless oil usingthe compound (0.69 g) obtained in (Example 16)<Step 1>.

<Step 3> Synthesis of2-chloro-4-((2′,6′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)anilinehydrochloride

To a solution of the compound (0.78 g) obtained in (Example 16)<Step 2>in ethyl acetate (3.0 mL), a solution of 4M hydrogen chloride in ethylacetate (2.23 mL) was added and the resultant reaction mixture wasstirred at room temperature for 3 hours. The precipitate was collectedby filtration and dried under reduced pressure to give the titlecompound (0.47 g) as a white solid.

<Step 4> Synthesis of ethyl2-((2-chloro-4-((2′,6′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)phenyl)amino)acetate

In accordance with the method in (Example 14)<Step 3>, the titlecompound (357 mg) was obtained as a pale yellow oil using the compound(0.40 g) obtained in (Example 16)<Step 3> and ethyl 2-bromoacetate (0.24mL)<

Step 5> Synthesis of ethyl2-((2-chloro-4-((2′,6′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)phenyl)(sulfamoyl)amino)acetate

In accordance with the methods in (Example 14)<Step 4> and (Example14)<Step 5>, a mixture (839 mg) containing the title compound wasobtained as a brown oil using the compound (0.34 g) obtained in (Example16)<Step 4>.

<Step 6> Synthesis of5-[2-chloro-4-[[3-(2,6-dimethylphenyl)phenyl]methoxy]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one

In accordance with the method in (Example 15)<Step 6>, the titlecompound (46 mg) was obtained as a pale brown amorphous solid using thecompound (0.80 g) obtained in (Example 16)<Step 5>.

Example 17 Synthesis of5-[4-[[3-(2,6-dimethylphenyl)phenyl]methoxy]-2-methylphenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one<Step 1> Synthesis of (4-hydroxy-2-methylphenyl)carbamic acid tert-butylester

In accordance with the method in (Example 16)<Step 1>, the titlecompound (1.71 g) was obtained as a pale brown amorphous solid using4-amino-3-methylphenol (1.0 g).

<Step 2> Synthesis of(4-((2′,6′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-2-methylphenyl)carbamicacid tert-butyl ester

In accordance with the method in (Example 16)<Step 2>, the titlecompound (0.70 g) was obtained as a colorless amorphous solid using thecompound (0.40 g) obtained in (Example 17)<Step 1>.

<Step 3> Synthesis of4-((2′,6′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-2-methylanilinehydrochloride

In accordance with the method in (Example 16)<Step 3>, the titlecompound (0.47 g) was obtained as a white solid using the compound (0.65g) obtained in (Example 17) <Step 2>.

<Step 4> Synthesis of ethyl2-((4-((2′,6′-dimethyl-[1′,1′-biphenyl]-3-yl)methoxy)-2-methylphenyl)amino)acetate

In accordance with the method in (Example 16)<Step 4>, the titlecompound (0.31 g) was obtained as a brown oil using the compound (0.40g) obtained in (Example 17) <Step 3>.

<Step 5> Synthesis of ethyl2-((4-((2′,6′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-2-methylphenyl)(sulfamoyl)amino)acetate

In accordance with the method in (Example 16)<Step 5>, a mixture (895mg) containing the title compound was obtained as a brown oil using thecompound (0.30 g) obtained in (Example 17)<Step 4>.

<Step 6> Synthesis of5-[4-[[3-(2,6-dimethylphenyl)phenyl]methoxy]-2-methylphenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one

In accordance with the method in (Example 15)<Step 6>, the titlecompound (27 mg) was obtained as a brown amorphous solid using thecompound (0.85 g) obtained in (Example 17)<Step 5>.

Example 18 Synthesis of5-[4-[[3-(2,6-dimethylphenyl)phenyl]methoxy]phenyl]-4-methyl-1,1-dioxo-1,2,5-thiadiazolidin-3-one<Step 1> Synthesis of ethyl2-((4-((2′,6′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)phenyl)amino)propionate

In accordance with the method in (Example 14)<Step 3>, the titlecompound (0.56 g) was obtained as an orange oil from a hydrochloride(0.50 g) of the compound obtained in (Example 14)<Step 2> and ethyl2-bromopropionate (0.39 mL).

<Step 2> Synthesis of ethyl 2-(((N-(tert-butoxycarbonyl)sulfamoyl)(4-((2′,6′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)phenyl)amino)propionate

In accordance with the method in (Example 14)<Step 4>, a mixture (753mg) containing the title compound was obtained as a brown amorphoussolid using the compound (0.55 g) obtained in (Example 18)<Step 1>.

<Step 3> Synthesis of ethyl2-((4-((2′,6′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)phenyl)(sulfamoyl)amino)propionate

In accordance with the method in (Example 14)<Step 5>, a mixture (0.70g) containing the title compound was obtained as a brown amorphous solidusing the compound (0.74 g) obtained in (Example 18)<Step 2>.

<Step 4> Synthesis of5-[4-[[3-(2,6-dimethylphenyl)phenyl]methoxy]phenyl]-4-methyl-1,1-dioxo-1,2,5-thiadiazolidin-3-one

In accordance with the method in (Example 15)<Step 6>, the titlecompound (5 mg) was obtained as a pale yellow solid using the compound(0.30 g) obtained in (Example 18)<Step 3>.

Example 19 Synthesis of 5-[4-[[3-[2,6-dimethyl4-(3-methylsulfonylpropoxy)phenyl]phenyl]methoxy]phenyl]-1,1-dioxo-1,2-thiazolidin-3-one<Step 1> Synthesis of5-(4-((2′,6′-dimethyl-4′-(3-(methylsulfonyl)propoxy)-[1,1′-biphenyl]-3-yl)methoxy)phenyl)isothiazol-3(2H)-one1,1-dioxide

To a solution of the compound (50 mg) obtained in (Example 13)<Step 5>in methanol (5.0 mL), water (0.5 mL) and OXONE (registered trademark)(117 mg) were added and the resultant reaction mixture was stirred at40° C. for 18 hours. Subsequently, the mixture was stirred at 100° C.for 23 hours. The reaction mixture was allowed to reach room temperatureand water was added. The mixture was extracted with ethyl acetate. Theorganic phase was washed with brine and dried over anhydrous sodiumsulfate. From the organic phase, the solvent was removed by evaporationunder reduced pressure to give a mixture (50.0 mg) containing the titlecompound as a colorless solid.

<Step 2> Synthesis of5-[4-[[3-[2,6-dimethyl-4-(3-methylsulfonylpropoxy)phenyl]phenyl]methoxy]phenyl]-1,1-dioxo-1,2-thiazolidin-3-one

In accordance with the method in (Example 1)<Step 7>, the title compound(6.0 mg) was obtained as a colorless solid using the compound (50 mg)obtained in (Example 19)<Step 1>. The obtained compound is a racemicmixture.

Example 20 Synthesis of5-[4-[[3-[6-(3-hydroxy-3-methylbutoxy)-2,4-dimethylpyridin-3-yl]phenyl]methoxy]phenyl]-1,1-dioxo-1,2-thiazolidin-3-one

To a solution of the compound (50 mg) obtained in (Example 6) in acetone(5 mL), water (0.5 mL) and OXONE (registered trademark) (363 mg) wereadded and the resultant reaction mixture was stirred at 90° C. for 16hours. The reaction mixture was allowed to reach room temperature andwater was added. The mixture was extracted with ethyl acetate. Theorganic phase was washed with brine and dried over anhydrous sodiumsulfate. From the organic phase, the solvent was removed by evaporationunder reduced pressure and the resultant residue was purified by silicagel column chromatography (eluent; methylene chloride:methanol=20:1) togive the title compound (11 mg) as a colorless amorphous solid. Theobtained compound is a racemic mixture.

Example 21 Synthesis of5-[4-[[3-(2,6-dimethylphenyl)phenyl]methoxy]phenyl]-1,1-dioxo-1,2,6-thiadiazinan-3-one<Step 1> Synthesis of4((2′,6′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)benzaldehyde

To a solution of (2′,6′-dimethyl-[1,1′-biphenyl]-3-yl)methanol (1.0 g),4-hydroxybenzaldehyde (0.58 g), and triphenylphosphine (1.48 g) intetrahydrofuran (10 mL), a solution of 40% diisopropylazodicarboxylicacid diisopropyl in toluene (1.09 mL) was added under ice-cooling andthe resultant reaction mixture was stirred under ice-cooling for 3hours. A solution of diisopropyl azodicarboxylate in toluene (0.6 mL)was further added and the resultant reaction mixture was stirred at roomtemperature for 12 hours. From the reaction mixture, the solvent wasremoved by evaporation under reduced pressure to give a residue andwater was added to the resultant residue. The mixture was extracted withan organic solvent and the resultant organic phase was dried overanhydrous sodium sulfate. From the organic phase, the solvent wasremoved by evaporation under reduced pressure and the resultant residuewas purified by silica gel column chromatography (eluent;n-heptane:ethyl acetate=100:0 to 100:20) to give the title compound (1.2g) as a colorless oil.

<Step 2> Synthesis of ethyl3-amino-3-(4-((2′,6′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)phenyl)propionate

A mixed solution of the compound (1 g) obtained in (Example 21)<Step 1>,ammonium acetate (0.73 g), and monoethyl malonate (0.44 g) in ethanol(15 mL) was heated and refluxed for 20 hours. The reaction mixture wasallowed to reach room temperature and a 2M sodium hydroxide aqueoussolution was added. The mixture was extracted with ethyl acetate. Theobtained organic phase was dried over anhydrous sodium sulfate. From theorganic phase, the solvent was removed by evaporation under reducedpressure and the resultant residue was purified by silica gel columnchromatography (eluent; n-heptane:ethyl acetate=100:0 to 100:20) to givethe title compound (0.28 g) as a yellow oil.

<Step 3> Synthesis of ethyl3-(4-((2′,6′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)phenyl)-3-(sulfamoyl)propionate

In accordance with the method in (Example 14)<Step 4>, a mixture (8 mg)containing the title compound was obtained as a pale yellow amorphoussolid using the compound (200 mg) obtained in (Example 21)<Step 2>.

<Step 4> Synthesis of5-[4-[[3-(2,6-dimethylphenyl)phenyl]methoxy]phenyl]-1,1-dioxo-1,2,6-thiadiazinan-3-one

In accordance with the method in (Example 15)<Step 6>, the titlecompound (3.2 mg) was obtained as a pale yellow solid using the compound(7.0 mg) obtained in (Example 21)<Step 3>. The title compound is aracemic mixture.

Example 22 Synthesis of5-[4-[[3-(2,6-dimethylphenyl)phenyl]methoxy]phenyl]-1,1-dioxo-1,2-thiazinan-3-one<Step 1> Synthesis of N,N-bis(4-methoxybenzyl)methanesulfonamide

To a solution of methanesulfonamide (5 g) in N,N-dimethylformamide (75mL), potassium carbonate (29.1 g) was added and the resultant reactionmixture was stirred at room temperature for 5 hours. To the solution,p-methoxybenzyl chloride (18.1 g) was added and the resultant reactionmixture was stirred at room temperature for 19 hours. To the reactionsolution, water was added and the mixture was extracted with ethylacetate. The obtained organic phase was dried over anhydrous sodiumsulfate. From the organic phase, the solvent was removed by evaporationunder reduced pressure to give the title compound (17.1 g) as a whitesolid.

<Step 2> Synthesis of2-(4-((2′,6′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)phenyl)-N,N-bis(4-methoxybenzyl)ethenesulfonamide

To a solution of the compound (1.19 g) obtained in (Example 22)<Step 1>in tetrahydrofuran (5.5 mL), a solution of 1M lithiumhexamethyldisilazide in tetrahydrofuran (8.29 mL) was added dropwise at−20° C. After stirring the mixture at −20° C. for 1 hour, a solution ofdiethyl chlorophosphate (0.51 mL) in tetrahydrofuran (3 mL) was addeddropwise. After stirring the mixture at −20° C. for 1 hour, a solutionof the compound (0.75 g) obtained in (Example 21)<Step 1> intetrahydrofuran (3 mL) was added dropwise. After stirring the mixture atroom temperature for 19 hours, 1M hydrochloric acid and water weresequentially added to the reaction solution and the mixture wasextracted with ethyl acetate. The obtained organic phase was washed withbrine and dried over anhydrous sodium sulfate. From the organic phase,the solvent was removed by evaporation under reduced pressure and theresultant residue was purified by silica gel column chromatography(eluent; n-hexane:ethyl acetate=90:10 to 80:20) to give the titlecompound (890 mg) as a colorless oil.

<Step 3> Synthesis of dimethyl2-(2-(N,N-bis(4-methoxybenzyl)sulfamoyl)-1-(4-((2′,6′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)phenyl)ethyl)malonate

To a solution of dimethyl malonate (0.54 g) in tetrahydrofuran (6 mL), asolution of 28% sodium methoxide in methanol (0.81 g) was added and theresultant reaction mixture was stirred for 1 hour. Subsequently, asolution of the compound (0.87 g) obtained in (Example 22)<Step 2> intetrahydrofuran (4 mL) was added and the resultant reaction mixture washeated and refluxed for 17 hours. The reaction mixture was allowed toreach room temperature and a 10% citric acid aqueous solution was added.The mixture was extracted with ethyl acetate. The organic phase waswashed with brine and the resultant organic phase was dried overanhydrous sodium sulfate. From the organic phase, the solvent wasremoved by evaporation under reduced pressure and the resultant residuewas purified by silica gel column chromatography (eluent; n-hexane:ethylacetate=85:15 to 70:30) to give the title compound (730 mg) as a whiteamorphous solid.

<Step 4> Synthesis of methyl4-(N,N-bis(4-methoxybenzyl)sulfamoyl)-3-(4-((2′,6′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)phenyl)butanoate

To a solution of the compound (0.72 g) obtained in (Example 22)<Step 3>in N,N-dimethylformamide (6.0 mL), water (33.8 mg) and sodium chloride(54.92 mg) were added and the resultant reaction mixture was heated andrefluxed for 2.5 hours. The reaction mixture was allowed to reach roomtemperature and water was added. The mixture was extracted with ethylacetate. The organic phase was washed with brine and the resultantorganic phase was dried over anhydrous sodium sulfate. From the organicphase, the solvent was removed by evaporation under reduced pressure andthe resultant residue was purified by silica gel column chromatography(eluent; n-hexane:ethyl acetate=85:15 to 70:30) to give the titlecompound (358 mg) as a colorless oil.

<Step 5> Synthesis of methyl3-(4((2′,6′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)phenyl)-4-sulfamoylbutanoate

To a solution of the compound (0.32 g) obtained in (Example 22)<Step 4>in methylene chloride (3.0 mL), trifluoroacetic acid (0.60 mL) was addedand the resultant reaction mixture was stirred at room temperature for15 hours. The reaction solution was poured into a mixed solution of a10% potassium carbonate aqueous solution and ethyl acetate and themixture was extracted with ethyl acetate. The obtained organic phase waswashed with brine and then dried over anhydrous sodium sulfate. From theorganic phase, the solvent was removed by evaporation under reducedpressure and the resultant residue was purified by silica gel columnchromatography (eluent; n-hexane:ethyl acetate=75:25 to 65:35) to givethe title compound (150 mg) as a colorless oil.

<Step 6> Synthesis of5-[4-[[3-(2,6-dimethylphenyl)phenyl]methoxy]phenyl]-1,1-dioxo-1,2-thiazinan-3-one

To a mixed solution of the compound (140 mg) obtained in (Example22)<Step 5> in methanol (2 0 mL) and tetrahydrofuran (1.0 mL), asolution of 28% sodium methoxide in methanol (57.7 mg) was added and theresultant reaction mixture was stirred for 1 hour. To the reactionsolution, 1M hydrochloric acid was added and the mixture was extractedwith ethyl acetate. The obtained organic phase was washed with brine anddried over anhydrous sodium sulfate. From the organic phase, the solventwas removed by evaporation under reduced pressure and the resultantresidue was triturated with a mixed solution of n-hexane:ethylacetate=2:1 to give the title compound (93 mg) as a white solid. Thetitle compound is a racemic mixture.

Example 23 Synthesis of5-(4-(((R)-4-(6-(3-hydroxy-3-methylbutoxy)-2-methylpyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)oxy)phenyl)-1-oxo-1,2-thiazolidin-3-one(A)< <Step 1> Synthesis of4-(5-bromo-6-methylpyridin-2-yloxy)-2-methylbutan-2-ol

To a suspension of sodium hydride (containing about 40% of a mineraloil, 0.38 g) in N,N-dimethylformamide (10 mL),5-bromo-2-hydroxy-6-methylpyridine (1.00 g) and 3-hydroxy-3-methylbutyl4-methylbenzenesulfonate (1.51 g) were added under ice-cooling and theresultant reaction mixture was stirred at 60° C. for 2.5 hours. To themixture, 3-hydroxy-3-methylbutyl 4-methylbenzenesulfonate (0.50 g) wasfurther added and the resultant reaction mixture was stirred at 60° C.for 1.5 hours. Sodium hydride (containing about 40% of a mineral oil, 40mg) was further added. To the reaction mixture, a saturated aqueousammonium chloride solution was added and the mixture was extracted withethyl acetate. The organic phase was washed with brine and then driedover anhydrous sodium sulfate. From the organic phase, the solvent wasremoved by evaporation under reduced pressure and the resultant residuewas purified by silica gel column chromatography (eluent; n-hexane:ethylacetate=50:50 to 33:67) to give the title compound (1.3 g) as a paleyellow oil.

<Step 2> Synthesis of4-[5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-6-methylpyridin-2-yl]oxy-2-methylbutan-2-ol

To a solution of the compound (2.85 g) obtained in (Example 23)<Step 1>and bis(neopentyl glycolate)diboron (2.82 g) in 1,4-dioxane (45 mL),potassium acetate (3.06 g) and a[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) —dichloromethane adduct (0.42 g) were added. The mixture was degassed andthen heated and refluxed for 16 hours. To the reaction mixture, water(200 mL) was added and the mixture was extracted with ethyl acetate (200mL). The organic phase was washed with brine (80 mL) and then dried overanhydrous sodium sulfate. From the organic phase, the solvent wasremoved by evaporation under reduced pressure and the resultant residuewas purified by silica gel column chromatography (eluent; n-hexane:ethylacetate=95:5 to 80:20) to give the title compound (2.2 g).

<Step 3> Synthesis of4-(((1R)-4-bromo-2,3-dihydro-1H-inden-1-yloxy)phenylboronic acidN-methyliminodiacetic acid ester

To a mixed solution of the compound (0.20 g) obtained in (ReferenceExample 1), (1S)-4-bromo-2,3-dihydro-1H-inden-1-ol (153 mg) that wascommercially available or could be obtained by a known method, andtri-n-butylphosphine (0.50 mL) in tetrahydrofuran (3 mL),1,1′-azobis(N,N-dimethylformamide) (0.35 g) was added under ice-cooling.The resultant reaction mixture was stirred at room temperature for 1.5hours. From the reaction mixture, the solvent was removed by evaporationunder reduced pressure and the resultant residue was purified by silicagel column chromatography (eluent; n-hexane:ethyl acetate=50:50 to0:100). From the eluted solution, the solvent was removed by evaporationunder reduced pressure to give a crude product containing the titlecompound.

<Step 4> Synthesis of5-(4-((1R)-4-bromo-2,3-dihydro-1H-inden-1-yloxy)phenypisothiazol-3-ol1-oxide (A)

In accordance with the method in (Example 1)<Step 6>, the title compound(24.6 mg) was obtained from the crude product (178 mg) obtained in(Example 23)<Step 3>.

<Step 5> Synthesis of3-hydroxy-5-(4-(((R)-4-(6-(3-hydroxy-3-methylbutoxy)-2-methylpyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)oxy)phenyl)isothiazole1-oxide (A)

A mixed solvent of the compound (50 mg) obtained in (Example 23)<Step4>, the compound (49.4 mg) obtained in (Example 23)<Step 2>,bis(dibenzylideneacetone)palladium (7.1 mg),2-dicyclohexylphosphino-2′,4′,6′=triisopropylbiphenyl (XPhos: 11.8 mg),potassium carbonate (34.2 mg), 1,4-dioxane (1.0 mL), and water (0.5 mL)was heated and refluxed for 4 hours. The reaction solution was extractedwith ethyl acetate and the organic phase was dried over anhydrous sodiumsulfate. From the organic phase, the solvent was removed by evaporationunder reduced pressure and the resultant residue was purified by silicagel column chromatography (eluent; ethyl acetate:methanol=100:0 to80:20). From the eluted solution, the solvent was removed by evaporationunder reduced pressure to give the title compound (12 mg) as a colorlessamorphous solid.

<Step 6> Synthesis of5-(4-(((R)-4-(6-(3-hydroxy-3-methylbutoxy)-2-methylpyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)oxy)phenyl)-1-oxo-1,2-thiazolidin-3-one(A)

In accordance with the method in (Example 7)<Step 2>, each diastereomerof the title compound was obtained from the compound (0.13 g) obtainedin (Example 23)<Step 5>.

Primary fraction (10.3 mg, white amorphous solid, retention time 5.85minutes (LC/MS), diastereomer a: Example 23 (A)-a)

Secondary fraction (3.3 mg, white amorphous solid, retention time 5.77minutes (LC/MS), diastereomer b: Example 23 (A)-b)

Example 24 Synthesis of5-[4-[[(1R)-4-[6-(3-hydroxy-3-methylbutoxy)-2,6-dimethylphenyl]-2,3-dihydro-1H-inden-1-yl]oxy]phenyl]-1-oxo-1,2-thiazolidin-3-one(A)< <Step 1> Synthesis of4-(4-bromo-3,5-dimethylphenoxy)-2-methylbutan-2-ol

A mixed solution of 3-hydroxy-3-methylbutyl 4-methylbenzenesulfonate(4.24 g) synthesized in accordance with the method described in [WO2009/067613 pamphlet, Example 308], 4-bromo-3,5-dimethylphenol (3.0 g),and potassium carbonate (3.09 g) in N,N-dimethylformamide (15 mL) wasstirred at 80° C. for 3 hours. To the reaction mixture, ethyl acetate(200 mL) and water (100 mL) were added and the mixture was extractedwith ethyl acetate. The organic phase was successively washed with water(50 mL) and brine (50 mL) and then dried over anhydrous sodium sulfate.From the organic phase, the solvent was removed by evaporation underreduced pressure and the resultant residue was purified by silica gelcolumn chromatography (eluent; n-hexane:ethyl acetate=80:20 to 70:30).From the eluted solution, the solvent was removed by evaporation underreduced pressure to give the title compound (3.9 g).

<Step 2> Synthesis of4-(4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-3,5-dimethylphenoxy)-2-methylbutan-2-ol

In accordance with the method in (Example 23)<Step 2>, the titlecompound (2.65 g) was obtained using the compound (3.90 g) obtained in(Example 24)<Step 1>.

<Step 3> Synthesis of5-[4-[[(1R)-4-[6-(3-hydroxy-3-methylbutoxy)-2,6-dimethylphenyl]-2,3-dihydro-1H-inden-1-yl]oxy]phenyl]isothiazol-3-ol1-oxide (A)

In accordance with the method in (Example 23)<Step 5>, the titlecompound (8 mg) was obtained as a pale yellow solid using the compound(50 mg) obtained in (Example 23)<Step 4> and the compound (0.12 g)obtained in (Example 24)<Step 2>.

<Step 4> Synthesis of5-[4-[[(1R)-4-[6-(3-hydroxy-3-methylbutoxy)-2,6-dimethylphenyl]-2,3-dihydro-1H-inden-1-yl]oxy]phenyl]-1-oxo-1,2-thiazolidin-3-one(A)

In accordance with the method in (Example 7)<Step 2>, each diastereomerof the title compound was obtained from the compound (0.17 g) obtainedin (Example 24)<Step 3>.

Primary fraction (34.3 mg, white amorphous solid, retention time 6.17minutes (LC/MS), diastereomer a: Example 24 (A)-a)

Secondary fraction (40.5 mg, white amorphous solid, retention time 6.08minutes (LC/MS), diastereomer b: Example 24 (A)-b)

Example 25 Synthesis of4-(((1R)-1-(4-(1-oxo-1,2-thiazolidin-3-on-5-yl)phenoxy)-2,3-dihydro-1H-inden-4-yl)oxy)benzonitrile (A)< <Step 1> Synthesis of2-(((S)-4-bromo-2,3-dihydro-1H-inden-1-yl)oxy)tetrahydro-2H-pyran

In methylene chloride (16.2 mL), 3,4-dihydro-2H-pyran (10.6 mL) wasdissolved. To the solution, a solution of 4M hydrogen chloride in1,4-dioxane (31.1 μL) was added and(1S)-4-bromo-2,3-dihydro-1H-inden-1-ol (10.0 g) that was commerciallyavailable or could be obtained by a known method was added. Theresultant reaction mixture was stirred at room temperature for 3 hours.To the reaction mixture, a saturated aqueous sodium hydrogen carbonatesolution (60 mL) was added and extracted with methylene chloride (60mL). The organic phase was washed with brine (60 mL) and dried overanhydrous sodium sulfate. From the organic phase, the solvent wasremoved by evaporation under reduced pressure and the resultant residuewas purified by silica gel column chromatography (eluent; n-hexane:ethylacetate=95:5). From the eluted solution, the solvent was removed byevaporation under reduced pressure to give the title compound (15 g).

<Step 2> Synthesis of5,5-dimethyl-2((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy-2,3-dihydro-1H-inden-4-yl)-1,3,2-dioxaborinane

To a solution of the compound (14.0 g) obtained in (Example 25)<Step 1>in 1,4-dioxane (213 mL),5,5,5′,5′-tetramethyl-2,2′-di(1,3,2-dioxaborinane) (17.3 g), potassiumacetate (18.8 g), and a1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride—dichloromethane complex (2.61 g) were sequentially added andthe resultant reaction mixture was heated and refluxed for 3 hours. Tothe reaction mixture, water (300 mL) was added and the mixture wasfiltered with Celite while washing the mixture with ethyl acetate (250mL). To the filtrate, brine (200 mL) was added and the mixture wasextracted with ethyl acetate (200 mL). The organic phase was dried overanhydrous sodium sulfate. From the organic phase, the solvent wasremoved by evaporation under reduced pressure and the resultant residuewas purified by silica gel column chromatography (eluent; n-hexane:ethylacetate=70:30). From the eluted solution, the solvent was removed byevaporation under reduced pressure to give the title compound (15.3 g)as an orange oil.

<Step 3> Synthesis of((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy-2,3-dihydro-1H-inden-4-yl)boronicacid

To a solution of the compound (8.20 g) obtained in (Example 25)<Step 2>in ethyl acetate (370 mL), water (1.10 L) was added and the resultantreaction mixture was stirred at room temperature for 16 hours. Liquidseparation of the reaction mixture was conducted and the organic phasewas washed with brine (200 mL) and dried over anhydrous sodium sulfate.From the organic phase, the solvent was removed by evaporation underreduced pressure and the resultant residue was purified by silica gelcolumn chromatography (eluent; n-hexane:ethyl acetate=90:10 to 50:50).From the eluted solution, the solvent was removed by evaporation underreduced pressure to give the title compound (3.00 g) as a yellowishwhite solid.

<Step 4> Synthesis of4-(((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)-2,3-dihydro-1H-inden-4-yl)oxy)benzonitrile

To a solution of the compound (0.50 g) obtained in (Example 25)<Step 3>in methylene chloride (16 mL), 4-hydroxybenzonitrile (0.19 g),copper(II) acetate (0.32 g), and triethylamine (1.16 mL) were added andthe resultant reaction mixture was stirred in an oxygen atmosphere atroom temperature for 3 days. The reaction mixture was filtered withCelite. From the filtrate, the solvent was removed by evaporation underreduced pressure and the resultant residue was purified by silica gelcolumn chromatography. From the eluted solution, the solvent was removedby evaporation under reduced pressure to give the title compound (0.42g) as a colorless oil.

<Step 5> Synthesis of(S)-4-((1-hydroxy-2,3-dihydro-1H-inden-4-yl)oxy)benzonitrile

The compound (0.40 g) obtained in (Example 25)<Step 4> was dissolved ina 1:1 mixed solvent (8.0 mL) of methanol and tetrahydrofuran. To thesolution, 1M hydrochloric acid (4.0 mL) was added and the resultantreaction mixture was stirred at room temperature for 18 hours. From thereaction mixture, the solvent was removed by evaporation under reducedpressure. To the residue, a 1M sodium hydroxide aqueous solution wasadded to make the mixture basic. The mixture was extracted with ethylacetate. The organic phase was washed with brine and then dried overanhydrous sodium sulfate. From the organic phase, the solvent wasremoved by evaporation under reduced pressure to give the title compound(0.29 g) as a colorless oil.

<Step 6> Synthesis of(R)-4-((4-(4-cyanophenoxy)-2,3-dihydro-1H-inden-1-yl)oxy)phenylboronicacid N-methyliminodiacetic acid ester

In accordance with the method in (Example 1)<Step 3>, a mixture (330 mg)containing the title compound was obtained as a white solid from thecompound (0.3 g) obtained in (Example 25)<Step 5>.

<Step 7> Synthesis of4-(((1R)-1-(4-(3-hydroxy-1-oxidoisothiazol-5-yl)phenoxy)-2,3-dihydro-1H-inden-4-yl)oxy)benzonitrile(A)

In accordance with the method in (Example 1)<Step 6>, the title compound(92 mg) was obtained as a pale yellow solid from the compound (0.2 g)obtained in (Example 25)<Step 6>.

<Step 8> Synthesis of4-(((1R)-1-(4-(1-oxo-1,2-thiazolidin-3-on-5-yl)phenoxy)-2,3-dihydro-1H-inden-4-yl)oxy)benzonitrile (A)

In accordance with the method in (Example 7)<Step 2>, each diastereomerof the title compound was obtained from the compound (130 mg) obtainedin (Example 25)<Step 7>.

Primary fraction (25.3 mg, white solid, retention time 5.65 minutes(LC/MS),

diastereomer a: Example 25 (A)-a)

Secondary fraction (31.4 mg, white solid, retention time 5.60 minutes(LC/MS), diastereomer b: Example 25 (A)-b)

Example 26 Synthesis of4-(((1R)-1-(4-(1,1-dioxo-1,2,6-thiadiazinan-3-on-5-yl)phenoxy)-2,3-dihydro-1H-inden-4-yl)oxy)benzonitrile<Step 1> Synthesis of ethyl 3-(4-hydroxyphenyl)-3-(2, 2,2-trifluoroacetamide) propionate

To a solution of ethyl 3-amino-3-(4-hydroxyphenyl)propionate (1.0 g)that was commercially available or could be obtained by a known methodin methylene chloride (0.41 mL), trifluoroacetic anhydride (0.70 mL) wasadded under 10° C. and the resultant reaction mixture was stirred atroom temperature for 5 hours. To the reaction mixture, pyridine (0.41mL) was added at under 10° C. and the resultant reaction mixture wasstirred at room temperature for 1 hour. To the reaction mixture,trifluoroacetic anhydride (0.70 mL) and pyridine (0.41 mL) were furtheradded and the resultant reaction mixture was stirred at room temperaturefor 15 hours. From the reaction mixture, the solvent was removed byevaporation under reduced pressure. The residue was diluted with ethylacetate (50 mL), then successively washed with 0.5M hydrochloric acid(50 ml) and water (50 mL), and dried over anhydrous sodium sulfate. Fromthe organic phase, the solvent was removed by evaporation under reducedpressure and the resultant residue was washed with hexane to give thetitle compound (900 mg) as a yellow solid.

<Step 2> Synthesis of ethyl3-(4-(((R)-4-(4-cyanophenoxy)-2,3-dihydro-1H-inden-1-yl)oxy)phenyl)-3-(2,2,2-trifluoroacetamide)propionate

In accordance with the method in (Example 23)<Step 3>, the titlecompound (680 mg) was obtained as a yellow oil using the compound (0.40g) obtained in (Example 26)<Step 1> and the compound (0.33 g) obtainedin (Example 25)<Step 5>.

<Step 3> Synthesis of ethyl3-amino-3-(4-(((R)-4-(4-cyanophenoxy)-2,3-dihydro-1H-inden-1-yl)oxy)phenyl)propionate

The compound (0.45 g) obtained in (Example 26)<Step 2> was dissolved inethanol (10 mL). To the solution, sodium borohydride (63.2 mg) was addedand the resultant reaction mixture was stirred at room temperature for16 hours. The reaction mixture was diluted with water (50 mL) andextracted with ethyl acetate (50 mL). The obtained organic phase wasdried over anhydrous sodium sulfate. From the organic phase, the solventwas removed by evaporation under reduced pressure and the resultantresidue was purified by silica gel column chromatography (eluent;n-hexane:ethyl acetate=0:100). From the eluted solution, the solvent wasremoved by evaporation under reduced pressure to give a mixture (290 mg)containing the title compound as a colorless solid.

<Step 4> Synthesis of ethyl3-(4-(((R)-4-(4-cyanophenoxy)-2,3-dihydro-1H-inden-1-yl)oxy)phenyl)-3-(sulfamoylamino)propionate

To a solution of chlorosulfonyl isocyanate in tetrahydrofuran, aqueoustetrahydrofuran was added under 10° C. The reaction mixture was stirredat room temperature for 30 minutes to prepare a solution of sulfamoylchloride in tetrahydrofuran. A solution of the compound obtained in(Example 26)<Step 3> in tetrahydrofuran was prepared in anothercontainer. To the container, pyridine (0.10 ml) was added and thesolution of sulfamoyl chloride in tetrahydrofuran was added dropwiseunder 10° C. The resultant reaction mixture was stirred at roomtemperature for 19 hours. To the reaction mixture, water (30 mL) wasadded. The mixture was extracted with ethyl acetate (20 mL) twice. Theobtained organic phase was washed with water (20 mL) and dried overanhydrous sodium sulfate. From the organic phase, the solvent wasremoved by evaporation under reduced pressure and the resultant residuewas purified by silica gel column chromatography. From the elutedsolution, the solvent was removed by evaporation under reduced pressureto give the title compound.

<Step 5> Synthesis of4-(((1R)-1-(4-(1,1-dioxo-1,2,6-thiadiazinan-3-on-5-yl)phenoxy)-2,3-dihydro-1H-inden-4-yl)oxy)benzonitrile

The compound (15 mg) obtained in (Example 26)<Step 4> was dissolved inethanol (1.5 mL) and a 1M sodium hydroxide aqueous solution (0.15 mL)was added to the solution. The resultant reaction mixture was stirred atroom temperature for 2 hours. To the reaction mixture, a saturatedaqueous ammonium chloride solution (1 mL) and water (1 mL) were added.The mixture was extracted with ethyl acetate (10 mL) and the organicphase was dried over anhydrous sodium sulfate. From the organic phase,the solvent was removed by evaporation under reduced pressure and theresultant residue was purified by silica gel column chromatography(eluent; n-hexane:ethyl acetate=0:100). From the eluted solution, thesolvent was removed by evaporation under reduced pressure to give thetitle compound (7.5 mg) as a colorless amorphous solid.

Each compound of (Example 27) to (Example 28) below was synthesized bythe same method or a similar method in (Example 1) or (Example 26).

Example 275-(4-(((R)-4-phenoxy-2,3-dihydro-1H-inden-1-yl)oxy)phenyl)-1-oxo-1,2-thiazolidin-3-oneExample 285-(44(7-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)oxy)phenyl)-1-oxo-1,2-thiazolidin-3-oneExample 29 Synthesis of5-(4-(((R)-4-bromo-2,3-dihydro-1H-inden-1-yl)oxy)phenyl)-1-oxo-1,2-thiazolidin-3-one

To a solution of 1N L-Selectride in tetrahydrofuran (14.8 mL),tetrabutylammonium chloride (4.1 g) was added under ice-cooling and asolution of the compound (1 g) obtained in (Example 23)<Step 4> inanhydrous THF (5 mL) was added dropwise under 3° C. The reaction mixturewas allowed to reach room temperature and stirred for 2 days. To thereaction mixture, 1M hydrochloric acid was added. The mixture wasextracted with ethyl acetate. The organic phase was washed with brineand then dried over anhydrous sodium sulfate. From the organic phase,the solvent was removed by evaporation under reduced pressure and theresultant residue was purified by silica gel column chromatography(eluent; n-hexane:ethyl acetate) to give the title compound (0.44 g) asa yellow solid. The reduced title compound in this step is a mixture ofdiastereomers because the compound has a new asymmetric center (carbonatom).

Example 30 Synthesis of 5-(4-(((R)-4-(2,6-dimethyl4-(3-(methylsulfonyl)propoxy)phenyl)-2,3-dihydro-1H-inden-1-yl)oxy)phenyl)-1-oxo-1,2-thiazolidin-3-one<Step 1> Synthesis of2-bromo-1,3-dimethyl-5-(3-(methylsulfonyl)propoxy)benzene

In accordance with the method in (Example 23)<Step 1>, the titlecompound (289 g) was obtained as a white solid from4-bromo-3,5-dimethylphenol (217 g) and 3-(methylsulfonyl)propyl4-methylbenzenesulfonate (300 g).

<Step 2> Synthesis of2-(2,6-dimethyl-4-(3-(methylsulfonyl)propoxy)phenyl)-5,5-dimethyl-1,3,2-dioxaborinane

In accordance with the method in (Example 23)<Step 2>, the titlecompound (0.70 g) was obtained as a beige solid from the compound (1.0g) obtained in (Example 30)<Step 1>.

<Step 3> Synthesis of 5-(4-(((R)-4-(2,6-dimethyl4-(3-(methylsulfonyl)propoxy)phenyl)-2,3-dihydro-1H-inden-1-yl)oxy)phenyl)-1-oxo-1,2-thiazolidin-3-one

To a solution of the compound (0.10 g) in (Example 29), the compound(0.13 g) obtained in (Example 30)<Step 2>, potassium carbonate (34 mg),2-dicyclohexylphosphino-T,4′,6′-triisopropylbiphenyl (XPhos: 23 mg), andbis(dibenzylideneacetone)palladium (14 mg) in 1,4-dioxane (4 mL), water(2 mL) was added. The inside of the reaction system was purged withnitrogen and the resultant reaction mixture was heated and refluxed for2 hours. To the reaction mixture, a saturated aqueous ammonium chloridesolution was added. The mixture was extracted with ethyl acetate. Theorganic phase was washed with brine and then dried over anhydrous sodiumsulfate. From the organic phase, the solvent was removed by evaporationunder reduced pressure and the resultant residue was purified by silicagel column chromatography (eluent; n-hexane:ethyl acetate) to give thetitle compound (55 mg) as a pale yellow solid. The title compound is amixture of diastereomers because it has the asymmetric center as withthe compound in Example 29.

Example 31 Synthesis of 5-[4-[[3-[2,6-dimethyl4-(3-methylsulfonylpropoxy)phenyl]phenyl]methoxy]phenyl]-1,1-dioxo-1,2-thiazinan-3-one<Step 1> Synthesis ofN,N-bis((2-(trimethylsilyl)ethoxy)methyl)methanesulfonamide

Sodium hydride (4.6 g) was added to DMF (35 ml). To the solution, asolution of methanesulfonamide (5.0 g) in DMF (15 ml) was addeddropwise. (2-(chlorotrimethoxy)ethyl)trimethylsilane (18.6 ml) was addedto the solution and the resultant reaction mixture was stirred at roomtemperature for 2 hours. The reaction mixture was poured into ice waterand extracted with ethyl acetate. The organic phase was washed withbrine and then dried over anhydrous sodium sulfate. From the organicphase, the solvent was removed by evaporation under reduced pressure andthe resultant residue was purified by silica gel column chromatography(eluent; n-hexane:ethyl acetate) to give the title compound (7.4 g) as acolorless oil.

<Step 2> Synthesis of4-((2′,6′-dimethyl-4′-(3-(methylsulfonyl)propoxy)-[1,1′-biphenyl]-3-yl)methoxy)benzaldehyde

To a solution of the compound (3.0 g) in (Reference Example 2) in DMF(40 ml), potassium carbonate (1.2 g) and 4-hydroxybenzaldehyde (0.94 g)were added at room temperature. The inside of the reaction system waspurged with nitrogen and the mixture was heated and stirred at 80° C.for 2 hours. After the reaction mixture was allowed to cool to roomtemperature, water was added to the reaction mixture. The mixture wasextracted with ethyl acetate. The organic phase was washed with brineand then dried over anhydrous sodium sulfate. From the organic phase,the solvent was removed by evaporation under reduced pressure to givethe title compound (3.3 g) as a pale yellow oil.

<Step 3> Synthesis of(E)-2-(4-((2′,6′-dimethyl-4′-(3-(methylsulfonyl)propoxy)-[1,1′-biphenyl]-3-yl)methoxy)phenyl)-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)ethenesulfonamide

A solution of the compound (2.4 g) in (Example 31)<Step 1> in THF (7 ml)was cooled in an acetonitrile—dry ice bath. To the solution, a solutionof 1M lithium hexamethyldisilazane in THF (14.6 ml) was added dropwiseand the resultant reaction mixture was stirred at the same temperaturefor 50 minutes. Next, diethyl chlorophosphonate (1.1 ml) was addeddropwise and the resultant reaction mixture was further stirred for 90minutes. Then, a solution of the compound (3.0 g) in (Example 31)<Step2> in THF (10 ml) was added dropwise. The resultant reaction mixture wassitrred at the same temperature for 30 minutes, next stirred underice-cooling for 1 hour, then allowed to reach room temperature, andstirred for 1 hour. To the reaction mixture, 1M hydrochloric acid wasadded. The mixture was extracted with ethyl acetate. The organic phasewas washed with saturated aqueous sodium hydrogen carbonate, then washedwith a half saturated salt solution, and dried over anhydrous sodiumsulfate. From the organic phase, the solvent was removed by evaporationunder reduced pressure and the resultant residue was purified by silicagel column chromatography (eluent; n-hexane:ethyl acetate) to give thetitle compound (6.0 g) as a pale yellow oil.

<Step 4> Synthesis of dimethyl2-(2-(N,N-bis(2-(trimethylsilyl)ethoxymethyl)sulfamoyl)-1-(4-((2′,6′-dimethyl-4′-(3(methylsulfonyl)propoxy)-[1,1′-biphenyl]-3-yl)methoxy)phenyl)ethyl)malonate

To a solution of dimethyl malonate (1.5 ml) in THF (10 ml), a solutionof 28% sodium methoxide in methanol (2.6 g) was added at roomtemperature. The mixture was stirred for 10 minutes. To the reactionmixture, a solution of the compound (3.5 g) in (Example 31)<Step 3> inTHF (30 ml) was added and the resultant reaction mixture was heated andrefluxed for 65 hours. To the reaction mixture, a saturated aqueousammonium chloride solution was added. The mixture was extracted withethyl acetate. The organic phase was washed with saturated aqueoussodium hydrogen carbonate, then washed with brine, and dried overanhydrous sodium sulfate. From the organic phase, the solvent wasremoved by evaporation under reduced pressure and the resultant residuewas purified by silica gel column chromatography (eluent; n-hexane:ethylacetate) to give the title compound (3.5 g) as a colorless oil.

<Step 5> Synthesis of methyl4-(N,N-bis(2-(trimethylsilyl)-ethoxymethyl)sulfamoyl)-3-(4((2′,6′-dimethyl-4′-(3-(methylsulfonyl)propoxy)-[1,1′-biphenyl]-3-yl)methoxy)phenyl)butanoate

To a solution of the compound (3.5 g) in (Example 31)<Step 4> in DMF (35ml), sodium chloride (0.22 g) and water (0.14 ml) were added and theresultant reaction mixture was heated and refluxed for 17 hours. To thereaction mixture, water was added and the mixture was extracted withethyl acetate. The organic phase was washed with water, then washed withbrine, and dried over anhydrous sodium sulfate. From the organic phase,the solvent was removed by evaporation under reduced pressure to givethe title compound (3.0 g) as a colorless oil.

<Step 6> Synthesis of methyl3-(4-((2′,6′-dimethyl-4′-(3-(methylsulfonyl)propoxy)-[1,1′-biphenyl]-3-yl)methoxy)phenyl)-4-sulfamoylbutanoate

To a solution of the compound (1.5 g) in (Example 31)<Step 5> in aceticacid (15 ml), water (7.5 ml) was added and the resultant reactionmixture was heated and stirred at 80° C. for 3 hours. To the reactionmixture, water was added and the mixture was extracted with ethylacetate. The organic phase was washed with water, then washed withbrine, and dried over anhydrous sodium sulfate. From the organic phase,the solvent was removed by evaporation under reduced pressure and theresultant residue was purified by silica gel column chromatography(eluent; n-hexane:ethyl acetate) to give the title compound (0.34 g) asa colorless oil.

<Step 7> Synthesis of5-[4-[[3-[2,6-dimethyl-4-(3-methylsulfonylpropoxy)phenyl]phenyl]methoxy]phenyl]-1,1-dioxo-1,2-thiazinan-3-one

To a solution of the compound (20 mg) in (Example 31)<Step 6> inmethanol (0.40 ml), a solution of 28% sodium methoxide in methanol (8.3mg) was added at room temperature and the resultant reaction mixture wasstirred for 1 hour. To the reaction mixture, 1M hydrochloric acid wasadded and the mixture was extracted with ethyl acetate. The organicphase was washed with saturated aqueous sodium hydrogen carbonate, thenwashed with brine, and dried over anhydrous sodium sulfate. From theorganic phase, the solvent was removed by evaporation under reducedpressure to give the title compound (15 mg) as a colorless solid.

Example 32 Synthesis of4-(((1R)-1-(4-(1,1-dioxo-3-oxo-1,2-thiazinan-5-yl)phenoxy)-2,3-dihydro-1H-inden-4-yl)oxy)benzonitrile<Step 1> Synthesis of(E)-2-(4-(benzyloxy)phenyl)-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)ethenesulfonamide

In accordance with the method in (Example 31)<Step 3>, the titlecompound (6.1 g) was obtained as a colorless solid from the compound(7.5 g) obtained in (Example 31)<Step 1> and 4-benzyloxybenzaldehyde(4.5 g).

<Step 2> Synthesis of dimethyl2-(1-(4-(benzyloxy)phenyl)-2-(N,N-bis(2-(trimethylsilyl)-ethoxymethyl)sulfamoyl)ethyl)malonate

In accordance with the method in (Example 31)<Step 4>, the titlecompound (2.5 g) was obtained as a colorless oil from the compound (3.0g) obtained in (Example 32)<Step 1>.

<Step 3> Synthesis of methyl3-(4-(benzyloxy)phenyl)-4-(N,N-bis(2-(trimethylsilyl)-ethoxymethyl)sulfamoyl)butanoate

In accordance with the method in (Example 31)<Step 5>, the titlecompound (1.3 g) was obtained as a colorless oil from the compound (2.4g) obtained in (Example 32) <Step 2>.

<Step 4> Synthesis of methyl4-(N,N-bis(2-(trimethylsilyl)-ethoxymethyl)sulfamoyl)-3-(4-hydroxyphenyl)butanoate

To a solution of the compound (20 mg) in (Example 32)<Step 3> inmethanol (1.0 ml), 10% palladium—carbon (2.0 mg) was added and theresultant reaction mixture was stirred in a hydrogen atmosphere for 16hours. The inside of the reaction system was purged with nitrogen. Then,the reaction mixture was filtered with Celite. From the filtrate, thesolvent was removed by evaporation under reduced pressure to give thetitle compound (17 mg).

<Step 5> Synthesis of methyl4-(N,N-bis(2-(trimethylsilyl)-ethoxymethyl)sulfamoyl)-3-(4-(((R)-4-(4-cyanophenoxy)-2,3-dihydro-1H-inden-1-yl)oxy)phenyl)butanoate

A mixture of the compound (0.23 g) in (Example 25)<Step 5>, the compound(0.48 g) in (Example 32)<Step 4>, molecular sieves 3A (0.50 g), andtoluene (9.0 ml) was heated and refluxed. To the mixture,cyanomethylenetributylphosphorane (1.2 ml) was added dropwise and theresultant reaction mixture was heated and refluxed for 2.5 hours. Afterthe reaction mixture was allowed to cool to room temperature, thesolvent was removed by evaporation under reduced pressure and theresultant residue was purified by silica gel column chromatography(eluent; n-hexane:ethyl acetate) to give the title compound (0.25 g) asa pale yellow viscous oil.

<Step 6> Synthesis of4-(((1R)-1-(4-(1,1-dioxo-3-oxo-1,2-thiazinan-5-yl)phenoxy)-2,3-dihydro-1H-inden-4-yl)oxy)benzonitrile

To a solution of the compound (30 mg) in (Example 32)<Step 5> in THF(0.6 ml), a solution of 1M tetrabutylammonium fluoride in THF (0.15 ml)was added at room temperature. The resultant reaction mixture wasstirred at room temperature for 30 minutes, then heated and refluxed for1 hour, and stirred at room temperature for 16 hours. The reactionmixture was filtered and washed with ethyl acetate. To the obtainedorganic phase, 1M hydrochloric acid was added and the mixture wasextracted with ethyl acetate. The organic phase was washed with water,then washed with brine, and dried over anhydrous sodium sulfate. Fromthe organic phase, the solvent was removed by evaporation under reducedpressure and the resultant residue was purified by silica gel columnchromatography (eluent; methylene chloride:methanol) to give the titlecompound (3.2 mg) as a pale brown solid.

Example 33 Synthesis of5-(4-(((R)-4-bromo-2,3-dihydro-1H-inden-1-yl)oxy)phenyl)-1,1-dioxo-1,2-thiazinan-3-one<Step 1> Synthesis of(R)-4-((4-bromo-2,3-dihydro-1H-inden-1-yl)oxy)benzaldehyde

In accordance with the method in (Example 1)<Step 3>, the title compound(5.5 g) was obtained as a colorless solid from(S)-4-bromo-2,3-dihydro-1H-inden-1-ol (6.0 g) and 4-hydroxybenzaldehyde(3.5 g).

<Step 2> Synthesis of(R,E)-2-(4-((4-bromo-2,3-dihydro-1H-inden-1-yl)oxy)phenyl)-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)ethenesulfonamide

In accordance with the method in (Example 31)<Step 3>, the titlecompound (8.2 g) was obtained as a yellow oil from the compound (6.0 g)obtained in (Example 31)<Step 1> and the compound (5.4 g) obtained in(Example 33)<Step 1>.

<Step 3> Dimethyl2-(2-(N,N-bis(2-(trimethylsilyl)ethoxymethyl)sulfamoyl)-1-(4-(((R)-4-bromo-2,3-dihydro-1H-inden-1-yl)oxy)phenyl)ethyl)malonate

In accordance with the method in (Example 31)<Step 4>, the titlecompound (9.6 g) was obtained as a yellow oil from the compound (8.2 g)obtained in (Example 33)<Step 2>.

<Step 4> Synthesis of methyl4-(N,N-bis(2-(trimethylsilyl)ethoxymethyl)sulfamoyl)-3-(4-(((R)-4-bromo-2,3-dihydro-1H-inden-1-yl)oxy)phenyl)butanoate

In accordance with the method in (Example 31)<Step 5>, the titlecompound (5.9 g) was obtained as a colorless oil from the compound (9.6g) obtained in (Example 33) <Step 3>.

<Step 5> Synthesis of5-(4-(((R)-4-bromo-2,3-dihydro-11-1-inden-1-yl)oxy)phenyl)-1,1-dioxo-1,2-thiazinan-3-one

In accordance with the method in (Example 32)<Step 6>, the titlecompound (5.1 mg) was obtained as a pale brown solid from the compound(30 mg) obtained in (Example 33)<Step 4>.

Example 34 Synthesis of5-(4-(((R)-4-(4-(3-hydroxy-3-methylbutoxy)-2,6-dimethylphenyl)-2,3-dihydro-1H-inden-1-yl)oxy)phenyl)-1,1-dioxo-1,2-thiazinan-3-one

In accordance with the method in (Example 30)<Step 3>, the titlecompound (6.0 mg) was obtained as a white solid from the compound (17mg) obtained in (Example 33) and the compound (16 mg) obtained in(Example 24)<Step 2>.

Example 35 Synthesis of5-[4-[[3-[6-(3-hydroxy-3-methylbutoxy)-2,4-dimethylpyridin-3-yl]phenyl]methoxy]phenyl]-1,1-dioxo-1,2-thiazinan-3-one<Step 1> Synthesis of(E)-2-(4-((3-bromobenzyl)oxy)phenyl)-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)ethenesulfonamide

In accordance with the method in (Example 31)<Step 3>, the titlecompound (18 g) was obtained as a white solid from4-[(3-bromobenzyl)oxy]benzaldehyde (11 g) and the compound (13.4 g)obtained in (Example 31)<Step 1>.

<Step 2> Synthesis of dimethyl2-(2-(N,N-bis((2-(trimethylsilypethoxymethyl)sulfamoyl)-1-(4-((3-bromobenzyl)oxy)phenyl)ethyl)malonate

In accordance with the method in (Example 31)<Step 4>, the titlecompound (23 g) was obtained as a colorless oil from the compound (18 g)obtained in (Example 35)<Step 1>.

<Step 3> Synthesis of methyl 4-(N,N-bis(2-(trimethylsilyl)ethoxymethyl)sulfamoyl)-3-(4-((3-bromobenzyl)oxy)phenyl)butanoate

In accordance with the method in (Example 31)<Step 5>, the titlecompound (21 g) was obtained as a colorless oil from the compound (23 g)obtained in (Example 35)<Step 2>.

<Step 4> Synthesis of methyl3-(4((3-bromobenzyl)oxy)phenyl)-4-sulfamoylbutanoate

In accordance with the method in (Example 31)<Step 6>, the titlecompound (0.32 g) was obtained as a colorless oil from the compound (1.0g) obtained in (Example 35) <Step 3>.

<Step 5> Synthesis of5-(4-((3-bromobenzyl)oxy)phenyl)-1,2-thiazinan-3-one1,1-dioxide

In accordance with the method in (Example 31)<Step 7>, the titlecompound (0.12 g) was obtained as a white solid from the compound (0.16g) obtained in (Example 35) <Step 4>.

<Step 6> Synthesis of5-[4-[[3-[6-(3-hydroxy-3-methylbutoxy)-2,4-dimethylpyridin-3-yl]phenyl]methoxy]phenyl]-1,1-dioxo-1,2-thiazinan-3-one

In accordance with the method in (Example 30)<Step 3>, the titlecompound (29 mg) was obtained as a white solid from the compound (0.10g) obtained in (Example 35) <Step 5> and4-((5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-4,6-dimethylpyridin-2-yl)oxy)-2-methylbutan-2-ol(86 mg) synthesized by a similar method of (Example 23)<Step 2>.

The compounds shown below, the compounds of Formulae 9 to 12 ((Example1P) to (Example 157P)), compounds that can be obtained in combination ofPartial Structural Formulae shown in the aspect [1-19-1] to the aspect[1-19-2], salts of them, solvates of them, and optical isomers of themcan also be easily synthesized by using Production Methods above, themethods described in Examples, methods known by a person skilled in theart, or modified methods of them.

-   5-[4-[[3-[2,4-dimethyl-6-(3-methylsulfonylpropoxy)pyridin-3-yl]    phenyl]methoxy]phenyl]-1,1-dioxo-1,2-thiazolidin-3-one;-   5-[4-[[3-[2,4-dimethyl-6-(3-methylsulfonylpropoxy)pyridin-3-yl]phenyl]methoxy]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one;-   5-[4-[[3-[6-(3-hydroxy-3-methylbutoxy)-2,4-dimethylpyridin-3-yl]phenyl]methoxy]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one;-   5-[2-chloro-4-[[3-[2,6-dimethyl-4-(3-methylsulfonylpropoxy)phenyl]phenyl]methoxy]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one;-   5-[2-chloro-4-[[3-[2,4-dimethyl-6-(3-methylsulfonylpropoxy)pyridin-3-yl]    phenyl]methoxy]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one;-   5-[2-chloro-4-[[3-[6-(3-hydroxy-3-methylbutoxy)-2,4-dimethylpyridin-3-yl]    phenyl]methoxy]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one;-   5-[4-[[3-[2,6-dimethyl-4-(3-methylsulfonylpropoxy)phenyl]phenyl]methoxy]phenyl]-1,1-dioxo-1,2,6-thiadiazinan-3-one;-   5-[4-[[3-[2,4-dimethyl-6-(3-methylsulfonylpropoxy)pyridin-3-yl]    phenyl]methoxy] phenyl]-1,1-dioxo-1,2,6-thiadiazinan-3-one;-   5-[4-[[3-[6-(3-hydroxy-3-methylbutoxy)-2,4-dimethylpyridin-3-yl]phenyl]methoxy]phenyl]-1,1-dioxo-1,2,6-thiadiazinan-3-one    (Example 14P);-   5-[4-[[3-[2,4-dimethyl-6-(3-methylsulfonylpropoxy)pyridin-3-yl]phenyl]methoxy]phenyl]-1,1-dioxo-1,2-thiazinan-3-one;    and-   5-(4-((3-(2,6-dimethylphenyl)phenyl)methoxy)phenyl)-1,1-dioxo-1,2-thiazolidin-3-one    (Example 37P).

The structures of the final compounds synthesized in (Example 1) to(Example 35) above and the structures of the compounds in (Example 1P)to (Example 157P) are shown in the figures below (Structural Formulae 1to 12). LC/MS data and NMR data (no mark: 400 MHz NMR, *: 300 MHz NMR)of these final compounds of Examples are also shown in Tables below(Tables 2, 3, 7, and 8). The structures of the intermediate compoundssynthesized in Examples and the compounds of Reference Examples areshown in the figures below (Structural Formulae 13 to 19) and LC/MS dataof these intermediate compounds and the compounds of Reference Examplesand NMR data (no mark: 400 MHz NMR, *: 300 MHz NMR) of theseintermediate compounds and the compounds of Reference Examples are alsoshown in Tables below (Tables 4, 5, 6, 9, 10, 11, and 12). Here, withrespect to the intermediate compound, for example, the compound obtainedin Example 1 <Step 1> is expressed as “1-1”.

Structural Formula 1

Example No. Structure  1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

22

Structural Formula 2

Structural Formula 3

Structural Formula 4

Structural Formula 5

Structural Formula 6

Structural Formula 7

Structural Formula 8

Structural Formula 9

Structural Formula 10

Structural Formula 11

Structural Formula 12

Structural Formula 13

Example No. Substituted Phenylboronic Ester 1

2

3

4

5

6

7

8

9

Example No. Substituted Isothiazole 1

2

3

4

5

6

7

8

9

Structural Formula 14

Example No. Substituted Phenylboronic Ester 10

11

12

13

Example No. Substituted Isothiazole 10

11

12

13

Structural Formula 15

No. Structure 14-1

14-2

14-3

14-4

14-5

15-1

15-2

15-3

15-4

15-5

16-1

16-2

16-3

16-4

16-5

17-1

17-2

17-3

17-4

17-5

18-1

18-2

Structural Formula 16

No. Structure 18-3

19-1

21-1

21-2

21-3

22-1

22-2

22-3

22-4

22-5

Structural Formula 17

Structural Formula 18

Structural Formula 19

TABLE 2 Retention Example ESI-MS Time No. (M + 1)+ (Minute)  1 494 6.10 2 512 6.03  3 526 6.00  4 530* 5.98  5(A)-b 543 5.32  6(A)-b 509 5.77 7(A)-a 530* 6.20  8 480 5.79  9 496 5.33 10 510 5.42 11 479 3.90 12 4945.97 13(A)-a 542 5.62 14 445* 5.72# 15 559 6.50 16 456& — 17 436& — 18459* 5.65 19 558 5.82# 20 525 4.73# 21 437 6.20# 22 436 6.30 *(M + Na)+,#TFA system, &EI-MS(M+)

TABLE 3 MS-ESI (m/z) Retention Time Example [M + H]⁺ (Minute) 23-(A)-a521 5.85 23-(A)-b 521 5.77 24-(A)-a 534 6.17 24-(A)-b 534 6.08 25-(A)-a445 5.65 25-(A)-b 445 5.60 26 477# 5.72 27 442** 5.98 28 420**, # 5.3029 428, 430** 5.80, 5.92 30 590** 5.60# 31 572 5.82# 32 497 5.82# 33436, 438 6.05# 34 586** 6.31# 35 539 5.02# *[M + H]⁻ **[M + Na]⁺ #TFAsystem

TABLE 4 Substituted Substituted Phenylboronic Ester IsothiazoleRetention Retention Example ESI-MS Time ESI-MS Time No. (M + 1)+(Minute) (M + 1)+ (Minute) 1 532 5.87 492  6.08# 2 550 6.03 510  6.07# 3 586* 5.98 524  6.02# 4 546  5.95#  528* 6.05 5 581  4.32# 541  4.54# 6547 5.62 507 4.83 7  568* 6.02  528* 6.53 8 632  6.97# 478  5.77# 9 668*  6.97# 494  5.45# 10 588  6.07# 508 5.75 11 617 6.12 577 6.57 12574 6.15 492  6.01# 13 580 5.49 540 5.78 *(M + Na)+ #TFA system

TABLE 5 Retention Retention Retention ESI-MS Time ESI-MS Time ESI-MSTime No. (M + 1)+ (Minute) No. (M + 1)+ (Minute) No. (M + 1)+ (Minute)14-1 426* 6.72 14-2 304 5.57 14-3 418 6.72 14-4 619* 6.84 14-5 441 5.9815-1 562* 6.18 15-2 440 4.82 15-3 526 5.95 15-4 727* 6.18 15-5 605 5.7016-1 266* 5.05 16-2  460* 6.92 16-3 338 6.45 16-4 424  6.82 16-5 5036.38 17-1 246* 4.53 17-2  440* 6.65 17-3 318 5.95 17-4 404  6.68 17-5 505* 6.37 18-1 404  6.56 18-2  605* 6.72 18-3 483 6.35 19-1 556  6.22#21-1 339  6.45 21-2 404 4.42 21-3  505* 6.17 22-1 358* 5.40 22-2 6347.06 22-3  788* 6.80 22-4 730* 6.92 22-5 468 6.13

TABLE 6 MS-ESI Retention (m/z) Time Example [M + H]⁺ (Minute) 23-1 296**5.78 23-3 443*, # 5.75 23-5 519 6.08 24-1 309** 6.22 24-2 343** 5.9424-3 532 6.46 25-3 285** 5.18 25-4 358** 6.15 25-5 234# 5.18 25-6 481*5.57 25-7 443# 5.70 30-1 343, 345** 5.63 31-1 378** 6.52 31-2 475** 6.2031-3 813** 7.03 31-4 944** 6.85 31-5 886** 6.87 31-6 626** 5.63 32-1572** 7.06 32-2 704** 6.92 32-3 646** 7.03 32-4 556** 6.50 32-5 789**7.05 33-1 — 6.13 33-2 678, 680** 7.37 33-3 808, 810** 7.24 33-4 750,752** 7.26 35-1 650, 652** 7.23 35-2 782, 784** 7.03 35-3 724, 726**7.10 35-4 464, 466** 5.55 35-5 432, 434** 5.78# Reference 433, 435**5.93 Example 2 *[M + H]⁻ **[M + Na]⁺ #TFA system

TABLE 7 Exam- ple NMR data (,: ppm) <400 MHz (*: 300 MHz)>  1 (CDCl₃) δ:7.42 (1H, t, J = 8 Hz), 7.40-7.32 (1H, m), 7.20-7.13 (1H, m), 7.17 (2H,d, J = 9 Hz), 7.12-7.07 (1H, m), 6.98 (2H, d, J = 9 Hz), 6.68 (2H, s),5.10 (2H, s), 4.41 (1H, d, J = 7 Hz), 4.13 (2H, t, J = 5 Hz), 3.80 (2H,t, J = 5 Hz), 3.62 (2H, q, J = 7 Hz), 3.55 (1H, d, J = 8 Hz), 2.91-2.84(1H, m), 1.97 (6H, s), 1.25 (3H, t, J = 7 Hz).  12* (CDCl₃) δ: 7.50-7.33(4H, m), 7.21-6.96 (4H, m), 6.68 (2H, s), 5.16-5.10 (2H, m), 4.53-4.39(1H, m), 4.26-4.07 (3H, m), 3.70- 3.52 (0.25H, m, isomer-1), 3.35-3.21(0.75H, m, isomer-2), 3.02- 2.83 (1H, m), 2.03-1.90 (2H, m), 2.00 (6H,s), 1.30 (3H, d, J = 6 Hz). 13 (DMSO-D₆) δ: 11.00 (1H, s), 7.48-7.35(2H, m), 7.22 (2H, d, J = 9 Hz), 7.14 (1H, s), 7.09-7.00 (3H, m), 6.70(2H, s), 5.16 (2H, s), 4.51 (1H, d, J = 8 Hz), 4.08 (2H, t, J = 6 Hz),3.52-3.39 (1H, m), 3.27 (2H, t, J = 8 Hz), 3.02 (3H, s), 2.80 (1H, d, J= 17 Hz), 2.19-2.08 (2H, m), 1.90 (6H, s).  14* (DMSO-D₆) δ: 7.50-7.37(2H, m), 7.22-6.88 (9H, m), 5.10 (2H, s), 3.90 (2H, s), 1.95 (6H, s). 16* (CDCl₃) δ: 7.57-7.28 (3H, m), 7.20-6.95 (6H, m), 6.95-6.80 (1H, m),5.07 (2H, s), 4.40 (2H, br s), 1.99 (6H, s).  17* (CDCl₃) δ: 7.48-7.28(3H, m), 7.20-7.01 (5H, m), 6.89-6.77 (2H, m), 5.08 (2H, s), 4.29 (2H,br s), 2.36 (3H, s), 2.00 (6H, s).  18* (CDCl₃) δ: 7.50-7.31 (4H, m),7.21-7.00 (7H, m), 5.14 (2H, s), 4.51 (1H, q, J = 7 Hz), 2.01 (6H, s),1.45 (3H, d, J = 7 Hz). 19 (DMSO-D₆) δ: 7.47-7.38 (2H, m), 7.20 (2H, d,J = 9Hz), 7.16 (1H, s), 7.05 (1H, dt, J = 7, 2 Hz), 6.96 (2H, d, J = 9Hz), 6.70 (2H, s), 5.14 (2H, s), 4.33 (1H, t, J = 8 Hz), 4.08 (2H, t, J= 6 Hz), 3.30-3.24 (1H, m), 3.02 (3H, s), 2.84 (1H, dd, J = 16, 8 Hz),2.63 (2H, dd, J = 16, 8 Hz), 2.17-2.10 (2H, m), 1.92 (6H, s). 21(DMSO-D₆) δ: 11.97 (1H, br s), 7.93 (1H, br s), 7.52-7.41 (2H, m), 7.37(2H, d, J = 9 Hz), 7.20 (1H, s), 7.18-7.08 (4H, m), 7.03 (2H, d, J = 9Hz), 5.19 (2H, s), 4.76-4.66 (1H, m), 2.80-2.66 (1H, m), 2.64-2.54 (1H,m), 1.95 (6H, s). 22 (CDCl₃) δ: 7.46 (1H, t, J = 8 Hz), 7.40 (1H, d, J =8 Hz), 7.22- 7.08 (7H, m), 6.99 (2H, d, J = 9 Hz), 5.13 (2H, s),3.81-3.69 (1H, m), 3.66-3.59 (1H, m), 3.45 (1H, dd, J = 14, 12 Hz),3.03-2.92 (1H, m), 2.82 (1H, dd, J = 17, 12 Hz), 2.01 (6H, s).

TABLE 8 Exam- ple NMR data (δ: ppm) <400MHz (*: 300 MHz)> 23 1H-NMR(CDCl₃) δ: 7.47-7.27 (4H, m), 7.22 (2H, d, J = 9 Hz), (A)-a 7.16 (1H, d,J = 6 Hz), 7.04 (2H, d, J = 9 Hz), 6.61 (1H, d, J = 8 Hz), 5.84-5.79(1H, m), 4.56 (2H, t, J = 6 Hz), 4.44 (1H, d, J = 8 Hz), 3.60 (1H, dd, J= 17, 8 Hz), 2.92-2.80 (1H, m), 2.91 (1H, d, 17 Hz), 2.71-2.60 (1H, m),2.60-2.49 (1H, m), 2.27 (3H, s), 2.19-2.09 (1H, m), 2.02 (2H, t, J = 6Hz), 1.32 (6H, s). 23 1H-NMR (CDCl₃) δ: 7.62 (1H, s), 7.45-7.29 (5H, m),7.16 (1H, (A)-b d, J = 6 Hz), 7.09 (2H, d, J = 9 Hz), 6.61 (1H, d, J = 8Hz), 5.86-5.82 (1H, m), 4.56 (2H, t, J = 6 Hz), 4.51 (1H, dd, J = 12, 7Hz), 3.30 (1H, dd, J = 17, 12 Hz), 2.98 (1H, dd, J = 17, 7 Hz),2.94-2.81 (1H, m), 2.73-2.51 (2H, m), 2.28 (3H, s), 2.21-2.11 (1H, m),2.02 (2H, t, J = 6 Hz), 1.32 (6H, s). 26 1H-NMR (CDCl3) δ: 7.62 (2H, d,J = 9 Hz), 7.38-7.30 (4H, m), 7.07 (2H, d, J = 9 Hz), 7.02 (1H, dd, J =4, 4 Hz), 6.99 (2H, d, J = 9 Hz), 5.86-5.79 (1H, m), 5.00-4.91 (1H, m),4.65 (1H, d, J = 11 Hz), 3.09 (1H, dd, J = 17, 4 Hz), 3.03-2.91 (1H, m),2.91 (1H, dd, J = 12, 17 Hz), 2.83-2.72 (1H, m), 2.67-2.55 (1H, m),2.27-2.15 (1H, m). 31 1H-NMR (CDCl3) δ: 7.48-7.34 (2H, m), 7.19-7.03(4H, m), 7.01-6.92 (2H, m), 6.64 (2H, s), 5.10 (2H, s), 4.18-4.06 (2H,m), 3.80-3.56 (2H, m), 3.53-3.37 (1H, m), 3.31-3.22 (2H, m), 3.01-2.90(1H, m), 2.97 (3H, s), 2.86-2.71 (1H, m), 2.42-2.29 (2H, m), 1.97 (6H,s). 35 1H-NMR (DMSO-D6) δ: 7.50-7.40 (2H, m), 7.23-7.16 (3H, m),7.15-7.10 (1H, m), 6.93 (2H, d, J = 9 Hz), 6.55 (1H, s), 5.13 (2H, s),4.37 (1H, s), 4.33 (2H, t, J = 7 Hz), 3.26-3.15 (1H, m), 2.94-2.79 (2H,m), 2.28-2.20 (1H, m), 2.19-2.09 (1H, m), 2.06 (3H, s), 1.90 (3H, s),1.82 (2H, t, J = 7 Hz), 1.16 (6H, s).

TABLE 9 Substituted Isothiazole Exam- ple NMR data (δ: ppm) <400 MHz (*:300 MHz)>  1-6 (DMSO-D₆) δ: 11.27 (1H, s), 7.80 (2H, d, J = 9 Hz),7.51-7.40 (2H, m), 7.24-7.16 (3H, m), 7.08 (1H, d, J = 7 Hz), 7.07 (1H,s), 6.71 (2H, s), 5.27 (2H, s), 4.10-4.05 (2H, m), 3.72-3.66 (2H, m),3.51 (2H, q, J = 7 Hz), 1.92 (6H, s), 1.14 (3H, t, J = 7 Hz) 12-5(DMSO-D₆) δ: 11.28 (1H, s), 7.83-7.76 (2H, m), 7.50-7.39 (2H, m),7.24-7.16 (3H, m), 7.08 (2H, d, J = 9 Hz), 6.68 (2H, s), 5.26 (2H, s),4.58-4.53 (1H, m), 4.09-3.95 (2H, m), 3.87-3.74 (1H, m), 1.91 (6H, s),1.81-1.68 (2H, m), 1.15-1.08 (3H, m) 13-5 (DMSO-D₆) δ: 7.79 (2H, d, J =9 Hz), 7.50-7.39 (2H, m), 7.23-7.16 (3H, m), 7.11-7.03 (2H, m), 6.71(2H, s), 5.26 (2H, s), 4.08 (2H, t, J = 6 Hz), 3.31-3.24 (2H, m), 3.03(3H, s), 2.19-2.09 (2H, m), 1.92 (6H, s)

TABLE 10 Substituted Boronic Ester Exam- ple NMR data (δ: ppm) <400 MHz(*: 300 MHz)>  1-3 (CDCl₃) δ: 7.45-7.35 (4H, m), 7.18 (1H, s), 7.11-7.06(1H, m), 6.99 (2H, d, J = 9 Hz), 6.69 (2H, s), 5.11 (2H, s), 4.16- 4.12(2H, m), 3.95 (2H, d, J = 16 Hz), 3.80 (2H, t, J = 5 Hz), 3.75 (2H, d, J= 16 Hz), 3.62 (2H, q, J = 7 Hz), 2.53 (3H, s), 1.98 (6H, s), 1.25 (3H,t, J = 7 Hz) 12-4 (CDCl₃) δ: 7.47-7.35 (4H, m), 7.17 (1H, s), 7.08 (1H,d, J = 7 Hz), 6.99 (2H, d, J = 9 Hz), 6.63 (2H, s), 5.20-5.06 (2H, m),5.12 (1H, s), 4.01 (2H, t, J = 6 Hz), 3.89 (2H, d, J = 16 Hz), 3.74 (2H,d, J = 16 Hz), 2.54 (3H, s), 2.12-1.99 (2H, m), 2.05 (3H, s), 1.98 (6H,s), 1.32 (3H, d, J = 6 Hz)  13-4* (DMSO-D₆) δ: 7.50-7.37 (2H, m), 7.33(2H, d, J = 9 Hz), 7.16 (1H, s), 7.10-7.02 (1H, m), 6.99 (2H, d, J = 9Hz), 6.70 (2H, s), 5.16 (2H, s), 4.30 (2H, d, J = 17 Hz), 4.14- 3.97(4H, m), 3.31-3.22 (2H, m), 3.03 (3H, s), 2.47 (3H, s), 2.20-2.07 (2H,m), 1.91 (6H, s)

TABLE 11 Exam- ple NMR data (δ: ppm) <400 MHz (*: 300 MHz)> 14-3 (CDCl₃)δ: 7.46-7.36 (2H, m), 7.21-7.12 (2H, m), 7.12-7.05 (3H, m), 6.84 (2H, d,J = 9 Hz), 6.55 (2H, d, J = 9 Hz), 5.03 (2H, s), 4.01 (1H, br s), 3.75(2H, s), 2.01 (6H, s), 1.47 (9H, s).  14-5* (CDCl₃) δ: 7.49-7.32 (4H,m), 7.22-7.05 (5H, m), 6.96 (2H, d, J = 9 Hz), 5.11 (2H, s), 5.00 (2H,br s), 4.45 (2H, s), 2.01 (6H, s).  18-3* (CDCl₃) δ: 7.49-7.28 (4H, m),7.22-7.04 (5H, m), 7.00-6.91 (2H, m), 5.11 (2H, s), 4.95 (1H, q, J = 8Hz), 4.25 (2H, q, J = 7 Hz), 2.01 (6H, s), 1.31 (3H, t, J = 7 Hz), 1.23(4H, d, J = 8 Hz).  21-2* (CDCl₃) δ: 7.49-7.36 (2H, m), 7.27 (2H, d, J =9 Hz), 7.22- 7.06 (5H, m), 6.94 (2H, d, J = 9 Hz), 5.10 (2H, s), 4.38(1H, dd, J = 8, 6 Hz), 4.13 (2H, q, J = 7 Hz), 2.70-2.59 (2H, m), 2.01(6H, s), 1.23 (3H, t, J = 7 Hz).  22-3* (CDCl₃) δ: 7.49-7.37 (2H, m),7.24-7.06 (11H, m), 6.90 (2H, d, J = 9Hz), 6.83 (4H, d, J = 9 Hz), 5.08(2H, s), 4.22 (2H, d, J = 15 Hz), 4.03-3.96 (1H, m), 4.03 (2H, d, J = 15Hz), 3.85 (1H, d, J = 8 Hz), 3.80 (6H, s), 3.70 (3H, s), 3.62-3.51 (1H,m), 3.55 (3H, s), 3.32 (1H, dd, J = 14, 8 Hz), 2.03 (6H, s).  22-4*(CDCl₃) δ: 7.51-7.37 (2H, m), 7.24-7.14 (6H, m), 7.14-7.08 (3H, m), 7.03(2H, d, J = 9 Hz), 6.90 (2H, d, J = 9 Hz), 6.85 (4H, d, J = 9 Hz), 5.09(2H, s), 4.31 (2H, d, J = 15 Hz), 4.11 (2H, d, J = 15 Hz), 3.81 (6H, s),3.76-3.63 (1H, m), 3.56 (3H, s), 3.25 (1H, dd, J = 14, 8 Hz), 3.10 (1H,t, J = 5 Hz), 3.05 (1H, dd, J = 5, 2 Hz), 2.69 (1H, dd, J = 16, 9 Hz),2.02 (6H, s). 22-5 (CDCl₃) δ: 7.46 (1H, t, J = 8 Hz), 7.39 (1H, d, J = 8Hz), 7.23- 7.15 (4H, m), 7.15-7.08 (3H, m), 6.96 (2H, d, J = 7 Hz), 5.10(2H, s), 4.23 (2H, br s), 3.82-3.71 (1H, m), 3.63 (3H, s), 3.54 (1H, dd,J = 14, 7 Hz), 3.39 (1H, dd, J = 14, 8 Hz), 2.94 (1H, dd, J = 16, 7 Hz),2.73 (1H, dd, J = 16, 7 Hz), 2.02 (6H, s).

TABLE 12 Exam- ple NMR data (δ: ppm) <400 MHz (*: 300 MHz)>  23-2*¹H-NMR (CDCl₃) δ: 7.92 (1H, d, J = 8 Hz), 6.51 (1H, d, J = 8 Hz), 4.55(2H, t, J = 6 Hz), 3.77 (4H, s), 2.64 (3H, s), 1.98 (2H, t, J = 6 Hz),1.29 (6H, s), 1.03 (6H, s). 23-4 ¹H-NMR (DMSO-d₆) 11.28 (1H, s), 7.83(2H, d, J = 9 Hz), 7.57 (1H, d, J = 8 Hz), 7.46-7.41 (1H, m), 7.27-7.19(1H, m), 7.23 (2H, d, J = 9 Hz), 7.11 (1H, s), 6.10 (1H, dd, J = 7, 4Hz), 3.11-2.97 (1H, m), 2.97-2.83 (1H, m), 2.71-2.58 (1H, m), 2.15-2.00(1H, m) 25-1 ¹H-NMR (CDCl₃) δ: 7.42-7.38 (3H, m), 7.28 (1H, d, J = 8Hz), 7.09 (2H, dt, J = 14, 6 Hz), 5.37 (1H, t, J = 6 Hz), 5.21 (1H, dd,J = 7, 5 Hz), 4.86-4.81 (2H, m), 4.03-3.93 (2H, m), 3.63-3.54 (2H, m),3.13-3.03 (2H, m), 2.86-2.77 (2H, m), 2.49-2.38 (2H, m), 2.21-2.13 (1H,m), 2.06-1.98 (1H, m), 1.91-1.78 (2H, m), 1.78-1.68 (2H, m), 1.68-1.47(8H, m). 25-2 ¹H-NMR (CDCl₃) δ: 7.72-7.68 (2H, m), 7.52 (1H, d, J = 7Hz), 7.40 (1H, d, J = 8 Hz), 7.24-7.16 (2H, m), 5.29 (1H, t, J = 6 Hz),5.13 (1H, dd, J = 7, 5 Hz), 4.87 (1H, t, J = 4 Hz), 4.83 (1H, dd, J = 5,3 Hz), 4.08-3.94 (2H, m), 3.75 (4H, s), 3.75 (4H, s), 3.62- 3.54 (2H,m), 3.33-3.22 (2H, m), 3.04-2.94 (2H, m), 2.42-2.32 (2H, m), 2.16-2.07(1H, m), 1.75-1.52 (13H, m), 1.02 (6H, s), 1.01 (6H, s).  26-1* 1H-NMR(DMSO-d6) δ: 9.84 (1H, d, J = 9 Hz), 9.42 (1H, s), 7.14 (2H, d, J = 8Hz), 6.70 (2H, d, J = 8 Hz), 5.17 (1H, ddd, J = 9 Hz, 9 Hz, 6 Hz),4.09-3.98 (2H, m), 2.92 (1H, dd, J = 16 Hz, 9 Hz), 2.80 (1H, dd, J = 16Hz, 6 Hz), 1.12 (3H, t, J = 7 Hz).  26-2* 1H-NMR (CDCl3) δ: 7.71 (1H, d,J = 9 Hz), 7.61 (2H, d, J = 9 Hz), 7.35-7.30 (2H, m), 7.26 (2H, d. J = 9Hz), 7.04-6.95 (5H, m), 5.79 (1H, dd, J = 7 Hz, 4 Hz), 5.45-5.35 (1H,m), 4.15 (2H, q, J = 7 Hz), 3.04-2.86 (3H, m), 2.83-2.68 (1H, m),2.66-2.51 (1H, m), 2.29-2.12 (1H, m), 1.23 (3H, t, J = 7 Hz).  26-3*1H-NMR (CD3OD) δ: 7.69 (2H, d, J = 9 Hz), 7.35-7.28 (4H, m), 7.06-6.96(5H, m), 5.85 (1H, dd, J = 7 Hz, 4 Hz), 4.29 (1H, dd, J = 7 Hz, 8 Hz),4.09 (2H, q, J = 7 Hz), 2.95-2.81 (1H, m), 2.80-2.50 (4H, m), 2.18-2.04(1H, m), 1.20 (3H, t, J = 7 Hz).  26-4* 1H-NMR (CDCl3) δ: 7.61 (2H, d, J= 9 Hz), 7.37-7.30 (4H, m), 7.06-6.95 (5H, m), 5.79 (1H, dd, J = 7 Hz, 4Hz), 5.48 (1H, d, J = 7 Hz), 4.94-4.84 (1H, m), 4.43 (2H, s), 4.13 (2H,q, J = 7 Hz), 3.03-2.84 (3H, m), 2.83-2.68 (1H, m), 2.66-2.50 (1H, m),2.27-2.12 (1H, m), 1.24 (3H, t, J = 7 Hz). 30-2 1H-NMR (CDCl3) δ: 6.48(2H, s), 4.07 (2H, t, J = 6 Hz), 3.77 (4H, s), 3.28-3.18 (2H, m), 2.93(3H, s), 2.36 (6H, s), 2.36-2.24 (2H, m), 1.09 (6H, s). 33-1 1H-NMR(CDCl3) δ: 9.90 (1H, s), 7.87 (2H, d, J = 9 Hz), 7.50 (1H, d, J = 8 Hz),7.37 (1H, d, J = 8 Hz), 7.15 (1H, t, J = 8 Hz), 7.09 (2H, d, J = 9 Hz),5.96-5.89 (1H, m), 3.23-3.12 (1H, m), 3.03-2.92 (1H, m), 2.70-2.59 (1H,m), 2.29-2.18 (1H, m). 35-5 1H-NMR (DMSO-D6) δ: 12.15 (1H, s), 7.64 (1H,s), 7.52 (1H, d, J = 8 Hz), 7.44 (1H, d, J = 8 Hz), 7.35 (1H, t, J = 8Hz), 7.30 (2H, d, J = 9 Hz), 6.98 (2H, d, J = 9 Hz), 5.11 (2H, s),3.84-3.73 (1H, m), 3.73-3.62 (1H, m), 3.62-3.49 (1H, m), 2.82-2.71 (1H,m), 2.71-2.60 (1H, m).

The invention claimed is:
 1. A compound of Formula (I):

wherein n is an integer of 0 to 2; p is an integer of 0 to 4; h is 1; j is an integer of 0 to 3; k is 0; a ring A is a C₆₋₁₄ aryl group which is optionally substituted with 1 to 5 L(s), a 3- to 14-membered heterocyclic group which is optionally substituted with 1 to 5 L(s), a C₅₋₇ cycloalkyl group which is optionally substituted with 1 to 5 L(s), a C₅₋₇ cycloalkenyl group which is optionally substituted with 1 to 5 L(s), a 6- to 14-membered Spiro ring group which is optionally substituted with 1 to 5 L(s), or a 2-phenylamino-2-oxoacetyl group which is optionally substituted with 1 to 5 L(s); a ring B is benzene ring; X is an oxygen atom, a sulfur atom, or —NR⁷—; J₁ is —CR^(11a)R^(11b)—; J₂ is —CR^(12a)R^(12b)—; R¹s are independently a group optionally selected from a halogen atom, a C₁₋₆ alkyl group which is optionally substituted with 1 to 5 substituent(s) RI, a C₂₋₆ alkenyl group which is optionally substituted with 1 to 5 substituent(s) RI, a C₂₋₆ alkynyl group which is optionally substituted with 1 to 5 substituent(s) RI, a C₁₋₆ alkoxy group which is optionally substituted with 1 to 5 substituent(s) RI, and a cyano group; R^(2a) and R^(2b) are independently a group optionally selected from a hydrogen atom, a halogen atom, a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, a C₂₋₆ alkynyl group, a C₁₋₆ alkoxy group, and a cyano group; R³, R⁴, R⁵, R⁶, and R⁷ are independently a group optionally selected from a hydrogen atom, a C₁₋₆ alkyl group, a halogenated C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, and a C₂₋₆ alkynyl group; R^(11a) and R^(11b) are independently a group optionally selected from a hydrogen atom, a halogen atom, a C₁₋₆ alkyl group, a halogenated C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, a C₂₋₆ alkynyl group, a C₁₋₆ alkoxy group, a halogenated C₁₋₆ alkoxy group, a C₂₋₇ alkanoyl group, and a carboxy group; R^(12a) and R^(12b) are independently a group optionally selected from a hydrogen atom, a halogen atom, a C₁₋₆ alkyl group, a halogenated C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, a C₂₋₆ alkynyl group, a C₁₋₆ alkoxy group, a halogenated C₁₋₆ alkoxy group, and a cyano group; with the proviso that in the cyclic amide structure moiety, there is not one of the substituents (R^(2b), R^(11b), or R^(12b)) on an atom to which the ring B is bonded; Ls are independently a group optionally selected from a halogen atom, —OH, an oxo group, a cyano group, a C₁₋₁₀ alkyl group which is optionally substituted with 1 to 5 substituent(s) RI, a C₂₋₁₀ alkenyl group which is optionally substituted with 1 to 5 substituent(s) RI, a C₂₋₁₀ alkynyl group which is optionally substituted with 1 to 5 substituent(s) RI, a C₁₋₁₀ alkoxy group which is optionally substituted with 1 to 5 substituent(s) RI, a C₂₋₁₀ alkenyloxy group which is optionally substituted with 1 to 5 substituent(s) RI, a C₂₋₁₀ alkynyloxy group which is optionally substituted with 1 to 5 substituent(s) RI, an aryl group which is optionally substituted with 1 to 5 substituent(s) RII, a heterocyclic group which is optionally substituted with 1 to 5 substituent(s) RII, an aralkyl group which is optionally substituted with 1 to 5 substituent(s) RII, a heteroarylalkyl group which is optionally substituted with 1 to 5 substituent(s) RII, a non-aromatic heterocyclic alkyl group which is optionally substituted with 1 to 5 substituent(s) RII, an aryloxy group which is optionally substituted with 1 to 5 substituent(s) RII, a heteroaryloxy group which is optionally substituted with 1 to 5 substituent(s) RII, a non-aromatic heterocyclic oxy group which is optionally substituted with 1 to 5 substituent(s) RII, an aralkyloxy group which is optionally substituted with 1 to 5 substituent(s) RII, a heteroarylalkyloxy group which is optionally substituted with 1 to 5 substituent(s) RII, —SH, —SF₅, a —S(O)_(i)R^(a) (i is an integer of 0 to 2) group, a —NR^(b)R^(c) group, and a substituted spiropiperidinylmethyl group; R^(a) is a C₁₋₆ alkyl group or a halogenated C₁₋₆ alkyl group; R^(b) and R^(c) are independently a group optionally selected from a hydrogen atom, a C₁₋₆ alkyl group, a halogenated C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, a C₂₋₆ alkynyl group, a C₂₋₇ alkanoyl group (the alkanoyl group is optionally substituted with —OH or a C₁₋₆ alkoxy group), a C₁₋₆ alkylsulfonyl group, an arylcarbonyl group, and a heterocyclic carbonyl group, where R^(b) and R^(c) optionally form together with a nitrogen atom to which they are bonded, a 3- to 8-membered cyclic group, where in the cyclic group, one or two carbon atom(s) is(are) optionally substituted with an atom optionally selected from an oxygen atom, a sulfur atom, and a nitrogen atom (the nitrogen atom is optionally substituted with a C₁₋₆ alkyl group which is optionally substituted with 1 to 5 substituent(s) RI) or with a carbonyl group, and the cyclic group is optionally further substituted with 1 to 5 substituent(s) RII; where the substituents RI are the same as or different from each other and are each a group optionally selected from a halogen atom, —OH, a cyano group, a C₁₋₆ alkoxy group (the C₁₋₆ alkoxy group is optionally substituted with 1 to 5 halogen atom(s), 1 to 5 —OH, 1 to 5 C₁₋₆ alkoxy group(s), 1 to 5 aryl group(s) (the aryl group is optionally substituted with 1 to 3 halogen atom(s)), 1 to 5 heterocyclic group(s) (the heterocyclic group is optionally substituted with 1 to 3 C₁₋₆ alkyl group(s) or 1 to 3 oxo group(s)), 1 to 5 —S(O)_(i)R^(a) (i is an integer of 0 to 2) group(s), 1 to 5 —SO₂NR^(d)R^(e) group(s), 1 to 5 —CONR^(d)R^(e) group(s), or 1 to 5 —NR^(b1)R^(c1) group(s)), a —NR^(b1)R^(c1) group, and a heterocyclic oxy group (the heterocyclic oxy group is optionally substituted with 1 to 3 C₁₋₆ alkyl group(s) or 1 to 3 oxo group(s)); the substituents RII are the same as or different from each other and are each a group optionally selected from the substituents RI, a C₁₋₆ alkyl group (the C₁₋₆ alkyl group is optionally substituted with 1 to 5 halogen atom(s), 1 to 5 —OH, 1 to 5 C₁₋₆ alkoxy group(s), 1 to 5 —S(O)_(i)R^(a) (i is an integer of 0 to 2) group(s), 1 to 5 —NR^(b1)R^(c1) group(s), 1 to 5 —SO₂NR^(d)R^(e) group(s), or 1 to 5 —CONR^(d)R^(e) group(s)), a C₂₋₆ alkenyl group, a C₂₋₇ alkanoyl group, an aralkyloxy group, a heterocyclic group (the heterocyclic group is optionally substituted with 1 to 3 C₁₋₆ alkyl group(s) or 1 to 3 oxo group(s)), a heterocyclic carbonyl group (the heterocyclic carbonyl group is optionally substituted with 1 to 3 C₁₋₆ alkyl group(s) or 1 to 3 oxo group(s)), a —S(O)_(i)R^(a) (i is an integer of 0 to 2) group, a —CONR^(d)R^(e) group, and a —CONR^(d)R^(e1) group; R^(d) and R^(e) are independently a hydrogen atom or a C₁₋₆ alkyl group (the C₁₋₆ alkyl group is optionally substituted with 1 to 5 halogen atom(s), 1 to 5 —OH, or 1 to 5 C₁₋₆ alkoxy group(s)); R^(e1) is a C₁₋₆ alkyl group (the C₁₋₆ alkyl group is substituted with 1 to 5 —OH, 1 to 5 C₁₋₆ alkoxy group(s), 1 to 5 aryl group(s) (the aryl group is optionally substituted with 1 to 3 halogen atom(s)), 1 to 5 heterocyclic group(s) (the heterocyclic group is optionally substituted with 1 to 3 C₁₋₆ alkyl group(s) or 1 to 3 oxo group(s)), 1 to 5 —S(O)_(i)R^(a) (i is an integer of 0 to 2) group(s), 1 to 5 —SO₂NR^(d)R^(e) group(s), 1 to 5 —CONR^(d)R^(e) group(s), or 1 to 5 —NR^(b1)R^(c1) group(s)); R^(b1) and R^(c1) are independently a group optionally selected from a hydrogen atom, a C₁₋₆ alkyl group, a C₂₋₇ alkanoyl group, and a C₁₋₆ alkylsulfonyl group, where R^(b1) and R^(c1) optionally form together with a nitrogen atom to which they are bonded, a 3 - to 8-membered cyclic group, where in the cyclic group, one or two carbon atom(s) is(are) optionally substituted with an atom optionally selected from an oxygen atom, a sulfur atom, and a nitrogen atom (the nitrogen atom is optionally substituted with a C₁₋₆ alkyl group) or with a carbonyl group, or a pharmaceutically acceptable salt of the compound.
 2. The compound according to claim 1 of Formula (I)-1:

wherein n, p, h, j, k, the ring A, X, J₂, R¹, R^(2a), R^(2b), R³, R⁴, R⁵, and R⁶ are the same as defined in Formula (I); a ring B′ is a benzene ring; and J_(1a) is CR^(11a), or a pharmaceutically acceptable salt of the compound.
 3. The compound according to claim 2 of Formula (II):

wherein n, p, h, j, k, X, J₂, R¹, R^(2a), R^(2b), R³, R⁴, R⁵, and R⁶ are the same as defined in Formula (I); the ring B′ and J_(1a) are the same as defined in Formula (I)-1; q and r are independently an integer of 0 to 4; s is an integer of 0 to 2 (with the proviso that q+s is an integer of 0 to 5); a ring A′ is an aryl group or a heteroaryl group; V is a single bond or an oxygen atom; R⁸s are independently a group optionally selected from a C₁₋₆ alkoxy group which is substituted with 1 to 5 substituent(s) M, a C₂₋₆ alkenyloxy group which is substituted with 1 to 5 substituent(s) M, a C₂₋₆ alkynyloxy group which is substituted with 1 to 5 substituent(s) M, a —CONR^(d)R^(e1) group, an aralkyloxy group, a heterocyclic oxy group (the heterocyclic oxy group is optionally substituted with 1 to 3 C₁₋₆ alkyl group(s) or 1 to 3 oxo group(s)), a heterocyclic group (the heterocyclic group is optionally substituted with 1 to 3 C₁₋₆ alkyl group(s) or 1 to 3 oxo group(s)), and a heterocyclic carbonyl group (the heterocyclic carbonyl group is optionally substituted with 1 to 3 C₁₋₆ alkyl group(s) or 1 to 3 oxo group(s)); the substituents M are independently a group optionally selected from a halogen atom, —OH, a C₁₋₆ alkoxy group, an aryl group (the aryl group is optionally substituted with 1 to 3 halogen atom(s)), a heterocyclic group (the heterocyclic group is optionally substituted with 1 to 3 —OH, 1 to 3 C₁₋₆ alkyl group(s), or 1 to 3 oxo group(s)), a —S(O)_(i)R^(a) (i is an integer of 0 to 2) group, a —NR^(b1)R^(c1) group, a —SO₂NR^(d)R^(e) group, and a —CONR^(d)R^(e) group; R⁹s and R¹⁰s are independently a group optionally selected from a halogen atom, —OH, a cyano group, a C₁₋₆ alkyl group which is optionally substituted with 1 to 5 substituent(s) RI, a C₂₋₆ alkenyl group which is optionally substituted with 1 to 5 substituent(s) RI, a C₂₋₆ alkynyl group which is optionally substituted with 1 to 5 substituent(s) RI, a C₁₋₆ alkoxy group which is optionally substituted with 1 to 5 substituent(s) RI, a C₂₋₇ alkanoyl group, —SH, a —S(O)_(i)R^(a) (i is an integer of 0 to 2) group, a —NR^(b1)R^(c1) group, and a —CONR^(d)R^(e) group; R^(a), R^(d), R^(e), R^(b1), R^(c1), R^(e1) are the same as defined in Formula (I), or a pharmaceutically acceptable salt of the compound.
 4. The compound according to claim 3, wherein X is an oxygen atom and any one of q and s is 1 or more, or a pharmaceutically acceptable salt of the compound.
 5. The compound according to claim 3 of Formula (II-1)-1:

wherein n, p, h, J₂, R¹, R^(2a), and R^(2b) are the same as defined in Formula (I); the ring B′ and J_(1a) are the same as defined in Formula (I)-1; q, r, s, R⁸, R⁹, and R¹⁰ are the same as defined in Formula (II); a ring A″ is a benzene ring, a pyridine ring, or a pyrimidine ring; broken lines indicate where the ring A″ or R⁸s are bonded; E is a group optionally selected from Formula (c1) to Formula (c6):

or a pharmaceutically acceptable salt of the compound.
 6. The compound according to claim 5, wherein E is Formula (c2), and any one of q and s is 1 or more, or a pharmaceutically acceptable salt of the compound.
 7. The compound according to claim 3 or 5, wherein s is 1, or a pharmaceutically acceptable salt of the compound.
 8. The compound according to claim 2 of Formula (III):

wherein n, p, h, j, k, J₂, X, R¹, R^(2a), R^(2b), R³, R⁴, R⁵, and R⁶ are the same as defined in Formula (I); the ring B′ and J_(1a) are the same as defined in Formula (I)-1; f is an integer of 0 to 2; g is an integer of 1 to 4; q1 is an integer of 0 to 3; q2 is 0 or 1; r1 is an integer of 0 to 2 (with the proviso that q1+q2+r1 is an integer of 0 to 5); a ring A′″ is a benzene ring or a pyridine ring; T is —CH₂—, an oxygen atom, —S(O)_(i)— (i is an integer of 0 to 2), or —NR⁷— (R⁷ is the same as R⁷ defined in Formula (I)); R¹³s are independently a group optionally selected from a halogen atom, —OH, a cyano group, a C₁₋₁₀ alkyl group which is optionally substituted with 1 to 5 substituent(s) RI, a C₂₋₁₀ alkenyl group which is optionally substituted with 1 to 5 substituent(s) RI, a C₂₋₁₀ alkynyl group which is optionally substituted with 1 to 5 substituent(s) RI, a C₁₋₁₀ alkoxy group which is optionally substituted with 1 to 5 substituent(s) RI, a C₂₋₁₀ alkenyloxy group which is optionally substituted with 1 to 5 substituent(s) RI, a C₂₋₁₀ alkynyloxy group which is optionally substituted with 1 to 5 substituents(s) RI, —SH, a —S(O)_(i)R^(a) (i is an integer of 0 to 2) group, and a —NR^(b)R^(c) group; R^(13a) is a group optionally selected from an aryl group which is optionally substituted with 1 to 5 substituent(s) RII, a heterocyclic group which is optionally substituted with 1 to 5 substituent(s) RII, an aralkyl group which is optionally substituted with 1 to 5 substituent(s) RII, a heteroarylalkyl group which is optionally substituted with 1 to 5 substituent(s) RII, a non-aromatic heterocyclic alkyl group which is optionally substituted with 1 to 5 substituent(s) RII, an aryloxy group which is optionally substituted with 1 to 5 substituent(s) RII, a heteroaryloxy group which is optionally substituted with 1 to 5 substituent(s) RII, a non-aromatic heterocyclic oxy group which is optionally substituted with 1 to 5 substituent(s) RII, an aralkyloxy group which is optionally substituted with 1 to 5 substituent(s) RII, a heteroarylalkyloxy group which is optionally substituted with 1 to 5 substituent(s) RII, and a substituted spiropiperidinylmethyl group; R¹⁴s are independently a group optionally selected from a halogen atom, —OH, a cyano group, a C₁₋₆ alkyl group which is optionally substituted with 1 to 5 substituent(s) RI, a C₂₋₆ alkenyl group which is optionally substituted with 1 to 5 substituent(s) RI, a C₂₋₆ alkynyl group which is optionally substituted with 1 to 5 substituent(s) RI, a C₁₋₆ alkoxy group which is optionally substituted with 1 to 5 substituent(s) RI, —SH, a —S(O)_(i)R^(a) (i is an integer of 0 to 2) group, and a —NR^(b)R^(c) group; R^(a), R^(b), R^(c), the substituent RI, and the substituent RII are the same as defined in Formula (I), or a pharmaceutically acceptable salt of the compound.
 9. The compound according to claim 8 of Formula (III-1)-1:

wherein n, p, h, J₂, R¹, R^(2a), and R^(2b) are the same as defined in Formula (I); J_(1a) is the same as defined in Formula (I)-1; q, s, the ring A′, V, R⁸, and R⁹ are the same as defined in Formula (II); q1, r1, T, R¹³, and R¹⁴ are the same as defined in Formula (III); Ea is Formula (c1) or Formula (c4) shown as E in Formula (II-1)-1, or a pharmaceutically acceptable salt of the compound.
 10. The compound according to claim 9, wherein Ea is Formula (c1), and any one of q and s is 1 or more, or a pharmaceutically acceptable salt of the compound.
 11. A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt of the compound.
 12. A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt of the compound; and a compound selected from the group consisting of a PPAR gamma agonist, a biguanide agent, a sulfonylurea, a rapid-acting insulin secretagogues, an alpha-glucosidase inhibitor, insulin or an insulin derivative, GLP-1 and a GLP-1 agonist, a DPP-IV inhibitor, an alpha-2 antagonist, an SGLT2 inhibitor, omega-3 fatty acids, an HMG-CoA reductase inhibitor, an HMG-CoA synthase inhibitor, a cholesterol absorption inhibitor, an acyl-CoA-cholesterol acyltransferase (ACAT) inhibitor, a CETP inhibitor, a squalene synthase inhibitor, an antioxidant, a PPAR alpha agonist, a PPAR delta agonist, an LXR agonist, an FXR agonist, an MTTP inhibitor, a squalene epoxidase inhibitor, a bile acid absorption inhibitor, a CB-1 receptor antagonist, a monoamine reuptake inhibitor, a serotonin reuptake inhibitor, a lipase inhibitor, a neuropeptide Y (NPY) receptor antagonist, a peptide YY (PYY) receptor antagonist, and an adrenergic beta-3 receptor agonist.
 13. The pharmaceutical composition of claim 12 wherein the DPP-IV inhibitor is selected from sitagliptin, vildagliptin, alogliptin, and saxagliptin, or a pharmaceutically acceptable salt thereof.
 14. The pharmaceutical composition of claim 12 wherein the DPP-IV inhibitor is sitagliptin, or a pharmaceutically acceptable salt thereof.
 15. A method for treating diabetes comprising the administration to a patient of an effective amount of the compound of claim 1, or a pharmaceutically acceptable salt of the compound.
 16. A method for treating diabetes comprising the administration to a patient of an effective amount of the compound of claim 1, or a pharmaceutically acceptable salt of the compound, and a compound selected from a group consisting of a PPAR gamma agonist, a biguanide agent, a sulfonylurea, a rapid-acting insulin secretagogue, an alpha-glucosidase inhibitor, insulin or an insulin derivative, GLP-1 and a GLP-1 agonist, a DPP-IVinhibitor, an alpha-2 antagonist, an SGLT2 inhibitor, omega-3 fatty acids, an HMG-CoA reductase inhibitor, an HMG-CoA synthase inhibitor, a cholesterol absorption inhibitor, an acyl-CoA-cholesterol acyltransferase (ACAT) inhibitor, a CETP inhibitor, a squalene synthase inhibitor, an antioxidant, a PPAR alpha agonist, a PPAR delta agonist, an LXR agonist, an FXR agonist, an MTTP inhibitor, a squalene epoxidase inhibitor, a bile acid absorption inhibitor, a CB-1 receptor antagonist, a monoamine reuptake inhibitor, a serotonin reuptake inhibitor, a lipase inhibitor, a neuropeptide Y (NPY) receptor antagonist, a peptide YY (PYY) receptor antagonist, and an adrenergic beta-3 receptor agonist.
 17. The method of claim 16 wherein the DPP-IV inhibitor is selected from sitagliptin, vildagliptin, alogliptin, saxagliptin, or a pharmaceutically acceptable salt thereof.
 18. The method of claim 16 wherein the DPP-IV inhibitor is sitagliptin, or a pharmaceutically acceptable salt thereof. 